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Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases
Open accessAbstract
As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.
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TL;DR
This review argues that clonally expanded mtDNA mutations arising from errors by the nuclear-encoded mtDNA replication machinery, rather than ROS-induced damage, are a major driving force behind aging and age-related diseases. It surveys Pol γ, PolG2, Twinkle, TFAM, MGME1, and RNase H1, linking their dysfunction to mtDNA mutagenesis, mitochondrial dysfunction, and diseases such as PEO and Parkinson’s disease.
Key findings
- mtDNA mutation rates are estimated at 10- to 17-fold higher than nuclear DNA, and over 85% of mutations detected in vivo could be recapitulated in vitro by purified human Pol γ, suggesting spontaneous replication errors account for most base-pair substitutions in mtDNA.
- The exonuclease-deficient Pol γ mtDNA mutator mouse shows a 3- to 8-fold increase in somatic point mutations, a 2000-fold higher mutation load than wild-type by random capture, and a 90-fold increase in circular mtDNA with large deletions excluding one hotspot; it develops a progeroid phenotype, whereas heterozygous mice have a 500-fold higher mutational burden than age-matched wild-type controls but no progeroid phenotype or reduced lifespan.
- Disease-associated replication-machinery defects include over 300 POLG mutations; PEO-associated Pol γ mutations R943H and Y955C cause a 99% decrease in polymerase activity, Y955C causes a 45-fold decrease in dNTP binding affinity, and G923D and A957S retain 21% and 23% of wild-type catalytic activity, respectively.
- Twinkle has 31 dominant and 3 recessive mutations recognized, mostly causing age-related disease; TFAM, MGME1, and RNase H1 defects are also linked to mtDNA depletion, replication stalling, PEO, neurodegeneration, or embryonic lethality in model systems.
Methods
- Narrative review of the literature on mtDNA replication machinery, mtDNA mutagenesis, aging, and age-related diseases.
- Synthesizes evidence from in vitro biochemistry, cultured cells, mouse models, Drosophila, C. elegans, and human patient studies.
- No systematic search strategy, inclusion/exclusion criteria, or meta-analysis is described.
Limitations
- The paper states that future studies focused on mechanisms of action are needed to effectively delay aging and prevent age-related diseases.
- The paper states that it remains controversial whether point mutations, deletions, or both drive the progeroid phenotype in mtDNA mutator mice, and that the timing of mtDNA mutations remains debated.
- Evident from the text: this is a narrative review without systematic methods, and many conclusions rely on animal models or correlative human data rather than uniform causal evidence.
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Claims the paper makes
128 Not checked yet · 33 Own interpretation · 13 No basis given · 1 Supported · 1 Partly supported · accuracy not yet measured
In the paper
“Preliminary data suggests that mtDNA shifting also occurs in aging skeletal muscle following resistance exercise training (Tarnopolsky, 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
- Not checked yetcites Tarnopolsky, 2009 source
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In the paper
“Here, we showed that deficiency and/or dysfunction in many of the nuclear-encoded mtDNA replication proteins, including Pol γ, PolG2, Twinkle, TFAM, MGME1 and RNase H1, results in age-related diseases and/or phenotypes both in vitro and in vivo.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
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In the paper
“Of the 17 human cellular DNA polymerases, polymerase gamma (Pol γ) is the only replicative polymerase known to function in mitochondrial DNA replication and repair (Bebenek and Kunkel, 2004; Ropp and Copeland, 1996; Sweasy et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
What the sources say
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In the paper
“Accumulations of mtDNA damage in the form of point mutations, deletions and depletions are correlated with aging and age-related diseases as observed in human skeletal muscle (Bua et al., 2006; Fayet et al., 2002), liver (Yen et al., 1991), brain (Corral-Debrinski et al., 1992a; Corral-Debrinski et al., 1994; Lin et al., 2002), heart (Corral-Debrinski et al., 1992b; Cortopassi and Arnheim, 1990),”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
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In the paper
“Early reports comparing nucleotide substitutions in mtDNA from somatic tissues of different primates revealed a 10-fold higher rate of evolution for mtDNA relative to the nuclear genome (Brown et al., 1979; Brown et al., 1982), implying a relatively high mutation rate for mtDNA.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
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In the paper
“In particular, much of the mtDNA damage is linked with the nuclear-encoded proteins responsible for its replication.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 1. Introduction
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In the paper
“We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > Abstract
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In the paper
“Conversely, G:C to T:A transversions are only a small fraction of the mutations found in aged Drosophila (Itsara et al., 2014) or humans (Kennedy et al., 2013; Zheng et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
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In the paper
“The most common oxidative lesions in mtDNA are the G:C to T:A transversion mutations caused by adenine pairing with the guanine adduct 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG) (Wang et al., 1998).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Wang et al., 1998 source
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In the paper
“Correlative evidence between increased levels of 8-oxo-dG and age-related deletions in mtDNA from humans (Capel et al., 2005; Hayakawa et al., 1992; Hayakawa et al., 1991), mice (Vermulst et al., 2007), rats (Sawada and Carlson, 1987) and houseflies (Sohal and Sohal, 1991) has been reported.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > Abstract
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In the paper
“More recently, estimates have increased the mutation rate from 10- to 17-fold higher in mtDNA than nuclear genomic (nDNA) (Tuppen et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Tuppen et al., 2010 source
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In the paper
“Therefore, effective and faithful mtDNA replication is necessary for cell survival.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
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In the paper
“The accessory subunit is required for enhanced DNA processivity by augmenting the affinity of the catalytic subunit for DNA (Lim et al., 1999; Young et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
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In the paper
“This is the exact scenario found in transgenic mice over-expressing mitochondrially-targeted human catalase, which decreases H2O2 (Schriner et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Schriner et al., 2005 source
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In the paper
“The Pol γ holoenzyme functions in conjunction with Twinkle, mtSSB, topoisomerase, mitochondrial RNA polymerase (POLRMT), RNase H1 and mitochondrial DNA ligase III (mtLigIII) to faithfully replicate mtDNA (Figure 2).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
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In the paper
“However, when manganese superoxide dismutase (MnSOD) and catalase are ectopically targeted to the mitochondrial matrix of transgenic flies, lifespan is decreased up to 43% (Bayne et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Bayne et al., 2005 source
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In the paper
“Additionally, mtDNA point mutations and deletions can disrupt mitochondrial function if the percentage of mutant mtDNA per cell reaches a threshold where not enough functional mitochondria remain to maintain proper energetic function (Wallace, 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
What the sources say
- Not checked yetcites Wallace, 1999 source
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In the paper
“The mixed results for whether ROS contributes to decreased or increased longevity may be explained by mitohormesis.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
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In the paper
“Thus, the data suggest that deletions are the driving force behind the progeroid phenotype of the mtDNA mutator mouse (Vermulst et al., 2008).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Vermulst et al., 2008 source
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In the paper
“For example, expression of an exonuclease-deficient Pol γ fusion protein in cultured human cells resulted in the accumulation of mtDNA point mutations (Spelbrink et al., 2000).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Spelbrink et al., 2000 source
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In the paper
“Excluding this hotspot, homozygous mutant mice showed a 90-fold increase in circular mtDNA with large deletions, as compared to WT controls.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Vermulst et al., 2008 source
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In the paper
“These mice also presented with secondary effects, such as increased apoptosis and cardiomyopathy (Zhang et al., 2005; Zhang et al., 2003).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In mice, transgenic overexpression of exonuclease-deficient Pol γ in cardiac tissue caused a greater than 23-fold increase in mtDNA point mutations and detectable levels of large mtDNA deletions (Zhang et al., 2000).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Zhang et al., 2000 source
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In the paper
“However, the first strong experimental evidence demonstrating a causal relationship between aging and the accumulation of mtDNA mutations/deletions secondary to an exonuclease-deficient Pol γ was obtained with the creation of the mtDNA mutator mouse.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
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- Rests on an assumption: The mtDNA mutator mouse progeroid phenotype is a valid model of mammalian aging.
In the paper
“This occurs despite presenting with a premature aging (progeroid) phenotype as evidenced by increased mitochondrial oxidative damage, cataracts and an impaired immune response (Van Remmen et al., 2003).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Van Remmen et al., 2003 source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the higher mutation load observed by the random capture method (2000-fold higher in the homozygous mtDNA mutator mouse than WT) showed that the heteroplasmic level of mutations clearly exceeded the bioenergetic threshold to elicit the premature aging phenotype.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
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In the paper
“Independently developed by two labs, the mtDNA mutator mouse has a homozygous knock-in that expresses a proofreading-deficient version of Pol γ, resulting in elevated levels of mtDNA mutations (Kujoth et al., 2005; Trifunovic et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As the only replicative DNA polymerase known to exist in mammalian mitochondria, Pol γ is likely to produce these spontaneous errors.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
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In the paper
“This suggests that spontaneous replication errors by Pol γ, and not ROS-induced damage, account for the majority of base pair substitution mutations in mtDNA.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
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In the paper
“Comparison of mutation spectrum in mtDNA derived from in vivo sources with DNA copied in vitro by the highly purified human Pol γ reveals that over 85% of mutation detected in vivo could be recapitulated in vitro by Pol γ (Zheng et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Zheng et al., 2006 source
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In the paper
“High fidelity is due to high nucleotide selectivity and exonucleolytic proofreading.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Longley et al., 2001 source
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In the paper
“The intrinsic 3′ → 5′ exonuclease activity of Pol γ improves replication fidelity at least 20-fold (Longley et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Longley et al., 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, at least at the level observed in the heterozygous mice, mtDNA point mutations do not limit natural lifespan.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
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In the paper
“The human catalytic subunit of Pol γ has high base substitution fidelity over short repeat sequences (< 3 nucleotides), as a misinsertion event only occurs approximately once in every 500,000 base pairs synthesized (Longley et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Longley et al., 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Mutations can also arise as spontaneous errors of replication during either DNA replication or repair events.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The progeroid phenotype and accumulated mutations of mtDNA mutator mice are not due to increased ROS production and oxidative stress (Trifunovic et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Trifunovic et al., 2005 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Four adPEO mutations (G923D, R943H, Y955C and A957S) were biochemically characterized (Graziewicz et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Graziewicz et al., 2004 source
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In the paper
“PolG2 is a 110 kDa homodimeric accessory subunit for the catalytic subunit PolG (Carrodeguas et al., 2001) that functions to enhance processivity of DNA replication by augmenting the binding of PolG to DNA (Lim et al., 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Lim et al., 1999 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Most of the women had early menopause or primary amenorrhea.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Luoma et al., 2004 source
plainn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“However, it was later determined that the substitution is probably a neutral polymorphism as it has a 1.1% frequency in controls (Luoma et al., 2007; Tiangyou et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Aberrant mitochondrial functioning has been implicated in the pathogenesis of idiopathic PD with genetic analysis focusing on age-related mtDNA mutations (Bender et al., 2006; Coxhead et al., 2015; Hudson et al., 2014; Keogh and Chinnery, 2015; Kraytsberg et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“PolG2 is a 110 kDa homodimeric accessory subunit for the catalytic subunit PolG (Carrodeguas et al., 2001) that functions to enhance processivity of DNA replication by augmenting the binding of PolG to DNA (Lim et al., 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Carrodeguas et al., 2001 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Several mitochondrial diseases have been linked to ineffective mtDNA replication by Pol γ.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The dominant Y955C mutation and two new missense mutations, N468D and A1105T, were discovered in these families (Luoma et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Luoma et al., 2004 source
plainn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, a similar analysis revealed no changes (Taanman and Schapira, 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Taanman and Schapira, 2005
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The proofreading deficient exonuclease domain causes a 10- to 100-fold increase in nucleotide misinsertion rates (Ponamarev et al., 2002).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Ponamarev et al., 2002 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In support of the latter study, another group reported that there is no contribution of common genetic variants of Pol γ contributing to the etiology of idiopathic PD (Tiangyou et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Tiangyou et al., 2006 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In fact, the overall fraction of deletions in tissues from the mtDNA mutator mouse was only measured to be ~1.0% (Kraytsberg et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Kraytsberg et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“PEO is associated with mtDNA point mutations and deletions (Hirano et al., 2001; Van Goethem et al., 2001; Van Goethem et al., 2003b) first identified in an Italian family with heritable autosomal dominant PEO (adPEO) (Zeviani et al., 1989).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A novel missense mutation in Pol γ (A2492G) was identified in another family with PEO, PD, hypogonadism, hearing loss, muscle weakness and psychiatric problems (Mancuso et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Mancuso et al., 2004 source
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite these two confounding studies, the role of Pol γ in contributing to mtDNA mutations and reduced copy number thus impacting the pathogenesis of PEO and PD patients appears convincing.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Lastly, Pol γ contains a polyglutamine tract in the N-terminal region encoded by a CAG-repeat and rare variants in the CAG-repeat were found in patients with idiopathic PD (Luoma et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Luoma et al., 2007 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Seven PEO families of various ethnic origins were reported to have Pol γ mutations with multiple mtDNA deletions (Luoma et al., 2004) and reduced mtDNA copy number (Gui et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
plaincorrelationaln = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, the absence of Lewy bodies in the substantia nigra has been found postmortem in patients with Pol γ associated PD (Moslemi et al., 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Moslemi et al., 1999 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mitochondrial fusion apparently allows the mtDNA mutator mouse to carry a higher mutational load without affecting respiratory function (Chen et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
- Not checked yetcites Chen et al., 2010 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Thus, bezafibrate has the potential to be a therapy for PEO patients (Yatsuga and Suomalainen, 2012).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Yatsuga and Suomalainen, 2012
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Though WT/G451E and WT/R369G localize to mtDNA like WT PolG2, bioenergetic analysis of transfected HEK-293 cells finds that both mutant cell lines have significantly reduced reserve capacity (Young et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Young et al., 2015 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting the mitochondrially located RNase H1 is essential for development”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.6. Ribonuclease H1 (RNase H1)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“signifying that WT mtDNA is important for maintaining mitochondrial function irrespective of mutant mtDNA proportions”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting TFAM could also be used as a therapeutic agent in neurodegenerative disorders.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus G451E PolG2 is a dominant negative mutation causing adPEO.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting TFAM as a potential therapeutic agent to combat heart failure.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Only heterozygotes have been clinically identified, and recent biochemical characterization of heterodimers has found that the WT/G451E heterodimer has significantly reduced stimulation of PolG processivity due to weaker binding to both PolG and DNA (Young et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Young et al., 2015 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data further indicate that Twinkle is essential for mtDNA replication.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The percentage of mutated mtDNA must be between 60% and 90% in a given cell before dysfunction is measurable (Edgar and Trifunovic, 2009)”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 7. The contribution of clonal expansion of mtDNA mutations to mitochondrial dysfunction
What the sources say
- Not checked yetcites Edgar and Trifunovic, 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The phenotype of the deletor mouse is strikingly similar to PEO patients, thus creating a PEO mouse model (Tyynismaa et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Tyynismaa et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Therefore, the authors agree that mtDNA mutations associated with premature aging occur from early, pre-existing deletions and not de novo deletions (Taylor et al., 2014).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 7. The contribution of clonal expansion of mtDNA mutations to mitochondrial dysfunction
What the sources say
- Not checked yetcites Taylor et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Skeletal muscle with reduced reserve capacity has muscle weakness and exercise intolerance, hallmarks of PEO.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The WT/R369G heterodimer functions like the wild-type enzyme in vitro.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Young et al., 2015 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting RNase H1 is vital for mtDNA replication”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.6. Ribonuclease H1 (RNase H1)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests TFAM could similarly be a therapeutic agent for diabetes.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Heart failure, myopathy, diabetes, neurodegeneration and PD are all age-related diseases strongly implicating TFAM in aging.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“further supporting the use of rhTFAM as a therapeutic agent”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonal expansion of mtDNA mutations has been described in numerous tissues from aged individuals, such as skeletal muscle (Fayet et al., 2002; Muller-Hocker et al., 1993), substantia nigra neurons (Cottrell et al., 2001; Kraytsberg et al., 2006), heart (Muller-Hocker, 1989) and colonic crypts (Taylor et al., 2003).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 7. The contribution of clonal expansion of mtDNA mutations to mitochondrial dysfunction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that TFAM is essential for mtDNA maintenance in vivo”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests Twinkle has an important role in maintenance of mtDNA higher order structures in adult human heart.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: MtDNA typically exists as monomeric double-stranded, covalently closed circles.
In the paper
“Heart tissue samples from patients harboring a Twinkle duplication mutation (amino acids 352–364) that causes adPEO have mtDNA that is lacking in these complex higher order structures (Pohjoismaki et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Pohjoismaki et al., 2010 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In mice, an RNase H1 knockout is embryonic lethal at E8.5 when mtDNA replication begins suggesting the mitochondrially located RNase H1 is essential for development (Cerritelli et al., 2003).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.6. Ribonuclease H1 (RNase H1)
What the sources say
- Not checked yetcites Cerritelli et al., 2003 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Conversely, systemic Twinkle overexpression in a transgenic mouse causes a significant increase in mtDNA copy number (Tyynismaa et al., 2004)”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Tyynismaa et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Systemic overexpression of Twinkle in mouse hearts causes an increase in complex DNA forms and recombination junctions similar to adult human hearts (Pohjoismaki et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Pohjoismaki et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“As expected, ageing is associated with decreases in both fission and fusion (Bereiter-Hahn, 2014; Chauhan et al., 2014; Jendrach et al., 2005; Seo et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Various types of exercise training verifiably improve mitochondrial oxidative function in aging and mitochondrial myopathic muscles (Irving et al., 2015; Jeppesen et al., 2006; Short et al., 2004; Short et al., 2003; Wenz et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Three different families presenting with PEO, skeletal muscle wasting/weakness, emaciation and respiratory distress bear MGME1 mutations (Kornblum et al., 2013).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.5. Mitochondrial Genome Maintenance Exonuclease 1 (MGME1)
What the sources say
- Not checked yetcites Kornblum et al., 2013 source
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Additionally, conditional deletion of Mfn1 and Mfn2 in mouse skeletal muscle correlates with increased accumulation of mtDNA point mutations and deletions (Chen et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
- Not checked yetcites Chen et al., 2010 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A homozygous Twinkle knock-out mouse is embryonic lethal at E8.5”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Milenkovic et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The homozygous knock-out is embryonic lethal at E8.5”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Not checked yetcites Larsson et al., 1998 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“TFAM overexpression in cardiomyocytes improves mitochondrial function when cells are exposed to hyperglycemic conditions (Suarez et al., 2008).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Not checked yetcites Suarez et al., 2008 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Overexpression of TFAM in these cells provides protection against Aβ1-42 induced mtDNA oxidative damage and MPP+ induced damage (Xu et al., 2009)”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Not checked yetcites Xu et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mice overexpressing Twinkle are protected from left ventricular remodeling in the heart (Tanaka et al., 2013).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Tanaka et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Crossing the MnSOD+/− mouse with the systemic Twinkle overexpression mouse abolishes the MnSOD+/− phenotype (Pohjoismaki et al., 2013).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Pohjoismaki et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“TFAM deletion in pancreatic β-cells leads to diabetic mice (Silva et al., 2000).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Not checked yetcites Silva et al., 2000 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, ROS does not appear to be the initiating or critical factor.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The theory of mitohormesis states that low levels of ROS are important signaling molecules that regulate stress response pathways and enhance longevity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, clonally expanded mtDNA mutations caused by replication errors leads to mitochondrial dysfunction.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The theory of mitohormesis states that low levels of ROS are important signaling molecules that regulate stress response pathways and enhance longevity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is this process, in conjunction with altered mitochondrial dynamics, that emerges as the driving force behind aging (Figure 4).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“These mice develop ventricular arrhythmia with aging due to dysfunctional ETC enzyme activity.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Baris et al., 2015 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The Twinkle duplication mouse, herein referred to as the deletor mouse, presents with mitochondrial myopathy around 12 months of age (Tyynismaa et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Tyynismaa et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“HeLa cells and patient fibroblasts with MGME1 knocked-down have increased amounts and lengths of 7S mtDNA (Nicholls et al., 2014).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.5. Mitochondrial Genome Maintenance Exonuclease 1 (MGME1)
What the sources say
- Not checked yetcites Nicholls et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 67
- Probably not a substantial claim. 16
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G (Craig et al., 2012; Longley et al., 2006; Young et al., 2011).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Partly supportedcites Craig et al., 2012 sourceExperimental — accuracy not yet measured
The Discussion reports that G451E p55 provided no enhancement of processivity, while the Results (§3.3) and Discussion report impaired processivity for R369G p55. This supports the comparison if R369G was intended, but the cited paper studies R369G, not the claim’s R396G. (LLM, conf=0.88)
- Not checked yetcites Longley et al., 2006 source
- Partly supportedcites Young et al., 2011 sourceExperimental — accuracy not yet measured
The Results section reports impaired stimulation of DNA synthesis by G451E and R369G, with G451E showing the more severe defect. The cited paper identifies the second variant as R369G, not R396G; it therefore does not support the comparison as written. No page number is available in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Another mouse model system crossed mice overexpressing TFAM with the mito-mice that have mutant mtDNA carrying a deletion of 4696 bp leading to an overall increase in mtDNA content and copy number without a decrease in the amount of deleted mtDNA (Nishiyama et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Supportedcites Nishiyama et al., 2010 source
The Introduction reports that the authors mated TFAM-overexpressing mice with mito-mice carrying a 4696-bp mtDNA deletion. The Results report 1.74 times as many total mtDNA copies in the resulting mice, while the Introduction says the proportion of pathogenic mtDNA remained unchanged. An unchanged proportion alongside increased total copies supports the claim that the amount of deleted mtDNA did not decrease. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
None of the sources cited for this claim have been checked yet.
In the paper
“The catalytic subunit has DNA polymerase, 3′→5′ exonuclease and 5′-dRP lyase activities (Graziewicz et al., 2006; Kaguni, 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Over-expression of genes involved in the maintenance of thiol redox homeostasis or co-overexpression of Cu-Zn superoxide dismutase (Cu-ZnSOD) and catalase increase the lifespan of Drosophila melanogaster by 33–48% (Orr et al., 2013; Orr and Sohal, 1994).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Orr et al., 2013 source
- Not checked yetcites Orr and Sohal, 1994
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, this suggests that ROS and 8-oxo-dG are not major contributors to mtDNA mutations in WT organisms.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“When either Cu-ZnSOD or catalase is over-expressed individually, only Cu-ZnSOD extends lifespan up to 48% while catalase has neutral or slightly negative effects (Sun and Tower, 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Sun and Tower, 1999
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, mice deficient in either Cu-ZnSOD or MnSOD have widespread oxidative damage and hepatocarcinogenesis or neurodegeneration with reduced lifespan (Elchuri et al., 2005; Lebovitz et al., 1996).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, when human catalase is localized to peroxisomes or targeted to the nucleus in mice, no detectable reduction in mtDNA damage or significant extension of lifespan are observed (Schriner and Linford, 2006; Schriner et al., 2000).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Schriner and Linford, 2006
- Not checked yetcites Schriner et al., 2000 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These same mice are also protected from mitochondrial dysfunction, decreased energy metabolism and lipid-induced insulin resistance in skeletal muscle (Lee et al., 2010).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Lee et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It encodes 37 mitochondrial genes: 22 transfer RNAs, 2 mitochondrial ribosomal RNAs and 13 proteins subunits of ETC complexes, with the exception of Complex II which is entirely nuclear encoded.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The ogg1 or ogg1/mth1 knock-out mice have 20-fold higher levels of 8-oxoguanine in mtDNA (de Souza-Pinto et al., 2001) and half the life expectancy relative to wild-type (WT) mice (Xie et al., 2004), but no increase in mtDNA mutations (Halsne et al., 2012).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The Pol γ holoenzyme is a heterotrimer consisting of a single 140 kDa catalytic subunit (nuclear encoded by POLG at chromosomal locus 15q25) and a 55 kDa accessory subunit that forms a dimer (nuclear encoded by POLG2 at chromosomal locus 17q24.1).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Human mtDNA is maternally inherited (Giles et al., 1980) and exists as a circular, double-stranded genome organized into 16,569 base pairs.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 2. Mitochondrial biology and genetics
What the sources say
- Not checked yetcites Giles et al., 1980 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Newer theories associate aging and mitochondrial dysfunction with clonally expanded mtDNA mutations caused by replication errors and altered mitochondrial dynamics.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 1. Introduction
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Support for the classical Mitochondrial Free Radical Theory of Aging (MFRTA) waned as new evidence linked ROS to both toxicity and signaling pathways associated with longevity.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 1. Introduction
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Kujoth et al. (2005) found no biomarkers of ROS induced damage to DNA, proteins or lipids, but report that tissue dysfunction is the result of apoptosis.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Kujoth et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As ROS gradually increase over time, so do the cumulative levels of mtDNA damages, with ROS eventually reaching unstoppable toxic concentrations resulting in further mitochondrial dysfunction and aging.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Trifunovic et al. (2004) also describe impaired OXPHOS with a reduction in ETC enzyme activities and decreased ATP production.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Trifunovic et al., 2004 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Similarly, while SOD knock-out mice (Sod2−/−) die within the first 10 days of life (Li et al., 1995), heterozygous mice (Sod2+/−) are viable with longevity and OXPHOS activity comparable to WT mice (Mansouri et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Li et al., 1995
- Not checked yetcites Mansouri et al., 2006 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In this theory, high levels of ROS promote mtDNA damage and the aged phenotype, while low levels of ROS are signaling molecules that regulate stress response pathways and activate cellular processes that enhance lifespan (Hekimi et al., 2011).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Hekimi et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a follow-up study to experimentally address the “vicious” cycle aspect of the MFRTA, mouse embryonic fibroblasts from mtDNA mutator mice are shown to produce normal amounts of ROS and demonstrate no increased sensitivity to oxidative stress (Trifunovic et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Trifunovic et al., 2005 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“On the other hand, inactivation of any of the five isoforms of SOD in Caenorhabditis elegans fails to decrease longevity, in spite of increased oxidative stress, and actually prolongs lifespan (Van Raamsdonk and Hekimi, 2012).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 3. MtDNA damage in aging: ROS versus replication errors
What the sources say
- Not checked yetcites Van Raamsdonk and Hekimi, 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Exonuclease-deficient Pol γ pancreatic islet cells caused impaired glucose tolerance, diabetes, and increased apoptosis in β-cells (Bensch et al., 2007; Bensch et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 4. Fidelity of DNA synthesis by pol γ
What the sources say
- Not checked yetcites Bensch et al., 2007 source
- Not checked yetcites Bensch et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The mice appear normal through adolescence but develop a progeroid phenotype including alopecia (hair loss) and graying, kyphosis (curvature of the spine), osteoporosis (loss of bone density), sarcopenia (loss of muscle mass), weight loss, reduced subcutaneous fat, presbycusis (hearing loss), reduced fertility, anemia, cardiac hypertrophy (heart enlargement), and a reduced lifespan.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Unlike the homozygous mtDNA mutator mice, mice heterozygous for the Pol γ mutation have no progeroid phenotype or reduced lifespan (Kujoth et al., 2005; Trifunovic et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“There are also no changes in the levels of antioxidants, protein carbonyls or aconitase enzyme activity in their tissues.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Trifunovic et al., 2005 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“WT and heterozygous mice mainly accumulate deletions at one hotspot between two 15-bp direct repeats, whereas homozygous mutant mice accumulate deletions regardless of the presence of direct repeats (Vermulst et al., 2008).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Vermulst et al., 2008 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, using an adaptation of the more sensitive “random capture method,” which relies on PCR amplification of single molecules for mutation detection but is not limited by polymerase fidelity, the heterozygous mice are found to have a 500-fold higher mutational burden than age-matched wild-type controls and a 30-fold increase over the oldest wild-type animals (Vermulst et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Vermulst et al., 2007 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Of the handful of heterozygous mutations identified in POLG2, G451E (Longley et al., 2006) and R369G (Craig et al., 2012; Young et al., 2011) are linked to PEO.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The resulting amino acid substitutions impair the stability of the ETC complexes, resulting in OXPHOS deficiency.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Edgar et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“To date, there are over 300 disease-associated mutations in POLG listed in the Human DNA Polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites http://tools.niehs.nih.gov/polg
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“PEO manifests during adulthood and is characterized by bilateral ptosis and progressive weakening of the external eye muscles, proximal muscle weakness and wasting, skeletal muscle with ragged red fibers, impaired ETC enzyme activity, exercise intolerance, sensory ataxic neuropathy and respiratory failure due to muscle fatigue.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a transgenic mouse model, human Pol γ encoding Y955C was targeted to the heart. These mice develop a molecular signature of PEO in the heart with cardiomyopathy, loss of mtDNA, increased 8-OHdG and premature death (Lewis et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Lewis et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Most of the mutations in Pol γ are associated with arPEO. They are compound heterozygotes and often occur with common Pol γ mutations, such as A467T (Van Goethem et al., 2003a), W748S (Van Goethem et al., 2004), R309L (Lamantea et al., 2002), G848S (Lamantea et al., 2002), R627W (Van Goethem et al., 2003a), N846S (Van Goethem et al., 2003c) or T251I in cis with P587L (Lamantea et al., 2002; Scud”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Both R943H and Y955C alter direct interactions with incoming dNTPs resulting in severely decreased processivity and a 99% decrease in polymerase activity.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Graziewicz et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Therefore, these fragments are surmised to arise from stalled replication due to Pol γ exonuclease deficiency and do not contribute to the progeroid phenotype (Kukat and Trifunovic, 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Kukat and Trifunovic, 2009
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In 2001, a heterozygous mutation in Pol γ that substituted a tyrosine with cysteine at codon 955 (Y955C) was first identified as a disease locus for adPEO while three more missense mutations were associated with arPEO (Van Goethem et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Van Goethem et al., 2001 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Two sisters with early-onset PD, peripheral neuropathy and without PEO had a 37% decrease in mtDNA content with multiple deletions and were found to be compound heterozygous for two missense mutations (G737R and R853W) in Pol γ (Davidzon et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Davidzon et al., 2006 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The Y955C mutation has a wild-type catalytic rate, but a 45-fold decrease in binding affinity for the incoming dNTP.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
What the sources say
- Not checked yetcites Ponamarev et al., 2002 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Patients with arPEO have the same clinical features as with adPEO, but with greater variation in symptoms and time of onset.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Edgar et al. (2009) reported frequent point mutations in ETC genes in homozygous mtDNA mutator mice, while heterozygous mice were not examined.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 5. Exonuclease-deficient pol γ mouse links mtDNA mutations and deletions to aging
What the sources say
- Not checked yetcites Edgar et al., 2009
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Some associated diseases manifest in adulthood and include symptoms of aging, namely autosomal dominant and recessive forms of Progressive External Ophthalmoplegia (adPEO/arPEO) and Parkinson’s disease.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.1. DNA Polymerase γ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests Twinkle provides cardioprotection and could be a potential therapy for heart failure patients.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A complete POLG2 knock-out is embryonic lethal in mice, but the heterozygous knockout (+/−) mouse has a normal phenotype (Humble et al., 2013).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Humble et al., 2013 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Twinkle is essential for mtDNA maintenance and copy number (Tyynismaa et al., 2004).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Tyynismaa et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Knockdown of porcine oocyte PolG2 causes an aging-like phenotype as evidenced by decreased production of ATP and maturation promoting factor (MPF), reducing the fraction of oocytes that reach MII stage (Lee et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
- Not checked yetcites Lee et al., 2015 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The N-terminal domain is important for ssDNA binding and stimulation of the C-terminal helicase activity (Farge et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Farge et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It was classified as a helicase based on sequence similarity to bacteriophage T7 gene 4 primase-helicase (T7 gp4) (Spelbrink et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Spelbrink et al., 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“MGME1 interacts directly with PolG suggesting a role in mtDNA replication, likely providing 5′ → 3′ exonuclease activity (Nicholls et al., 2014).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.5. Mitochondrial Genome Maintenance Exonuclease 1 (MGME1)
What the sources say
- Not checked yetcites Nicholls et al., 2014 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“G451E homodimers also fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Helicase activity along with strand annealing activity has been confirmed (Sen et al., 2012), but no primase activity has been detected to date.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Sen et al., 2012 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Twinkle has two domains, a primase-like N-terminal domain and a C-terminal helicase domain (Shutt and Gray, 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Shutt and Gray, 2006
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Twinkle is a 72 kDA hexamer/heptamer that functions as a 5′ → 3′ helicase for mtDNA replication (Korhonen et al., 2003).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Korhonen et al., 2003 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It is involved in D-loop formation and localizes to the nucleoid (Jemt et al., 2015; Milenkovic et al., 2013; Spelbrink et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In adult human hearts however, mtDNA has been shown to exist as dimers and is organized into highly complex, branched molecules (Pohjoismaki et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Pohjoismaki et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Knockdown of RNase H1 in human bone osteosarcoma cells (143B TK-) led to lower mtDNA copy number and complete stalling of replication (Ruhanen et al., 2011), suggesting RNase H1 is vital for mtDNA replication.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.6. Ribonuclease H1 (RNase H1)
What the sources say
- Not checked yetcites Ruhanen et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In all, 31 dominant and 3 recessive mutations have been recognized, the majority of which cause age-related disease (Sanchez-Martinez et al., 2012; Spelbrink et al., 2001).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Depletion of any of one these proteins results in severe dysfunction in respiratory capacity and fragmentation of mitochondria (Chen et al., 2005; Chen et al., 2010; Song et al., 2009)”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Overexpression of adPEO Twinkle mutations in HEK293 cells cause an accumulation of replication intermediates suggesting that these mutations are triggering replication stalling (Goffart et al., 2009; Wanrooij et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Originally, it was shown that CR decreases ROS production in rodents, particularly at Complex I, thereby preventing oxidative damage in mitochondria from heart (Gredilla et al., 2002), liver (Lopez-Torres et al., 2002), skeletal muscle (Lass et al., 1998) and brain (Sanz et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, others have reported that although oxidative capacity is improved, there are no changes in the mtDNA mutation load (Jeppesen et al., 2009; Taivassalo et al., 2006).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This activation is accomplished with either eccentric or concentric resistance exercise, as shown in a patient with the G12315A tRNAleu(CUN) point mutation, where resistance training significantly improved heteroplasmic ratios and increased the number of respiratory-competent fibers in muscle fibers (Taivassalo et al., 1999).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
- Not checked yetcites Taivassalo et al., 1999 source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, CR induces mitochondrial biogenesis and increases respiration through activation of sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase, and its downstream induction of PGC-1α (Chistiakov et al., 2014; Martin-Montalvo and de Cabo, 2013).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
- Not checked yetcites Chistiakov et al., 2014 source
- Not checked yetcites Martin-Montalvo and de Cabo, 2013
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Fusion and fission are opposing actions that work together to maintain the number, size, shape and function of mitochondria (Chan, 2012).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
- Not checked yetcites Chan, 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As with the fission and fusion processes, insufficient mitophagy and autophagy contribute to the accumulation of mutant mtDNA and are a factor in aging and age-related diseases (Gaziev et al., 2014; Green et al., 2011; Hubbard et al., 2012; Rubinsztein et al., 2011).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 8. Mitochondrial dynamics and aging
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“CR has been shown to extend both medium and maximum lifespan and delay the onset of age-related diseases in a variety of species, including yeast (Kaeberlein et al., 2007), C. elegans (Lee et al., 2006), rodents (Masoro, 2009) and Rhesus monkeys (Colman et al., 2014).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For all the targeted cell types, TFAM depletion leads to mtDNA depletion (not reported for midbrain DA neurons), mitochondrial transcript depletion (not reported for midbrain DA neurons) and respiratory chain deficiency, suggesting that TFAM is essential for mtDNA maintenance in vivo”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Aging is a multifactorial, progressive, biological process with mitochondria playing a central role.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The MFRTA, once at the forefront of aging theory, has lost favor since its fundamental notion of a “vicious” cycle of ROS generating ETC disruption, and hence more ROS, is based on anecdotal evidence.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Using Digital Deletion Detection (3D), a newer technology that allows for the study of rare, low occurring mtDNA deletions, Taylor et al. (2014) report that although the total deletion load increases in human brain with aging, the number and diversity of deletions remains constant.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 7. The contribution of clonal expansion of mtDNA mutations to mitochondrial dysfunction
What the sources say
- Not checked yetcites Taylor et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The deletor mouse phenotypes can be attenuated with a lipid-lowering agent, such as bezafibrate, however this treatment causes severe hepatic side effects (Yatsuga and Suomalainen, 2012).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Yatsuga and Suomalainen, 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“TFAM overexpression in rat pancreatic islet cells normalized Nd1 mRNA levels and restored glucose-induced ATP generation along with insulin secretion (Gauthier et al., 2009).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
- Not checked yetcites Gauthier et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“TFAM deletion in mouse pyramidal neurons causes mitochondrial late-onset neurodegeneration (MILON) (Sorensen et al., 2001) whereas deletion in mouse midbrain DA neurons leads to PD (Ekstrand et al., 2007).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.4. Transcription Factor A of Mitochondria (TFAM)
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This mouse attenuates VO-induced eccentric hypertrophy and improves cardiac function while suppressing the production of mitochondrial ROS and subsequent redox-sensitive signals (Ikeda et al., 2015).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.3. Twinkle
What the sources say
- Not checked yetcites Ikeda et al., 2015 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This does not imply that high levels of ROS do not contribute to the aging phenotype through oxidative damage to cellular components, such as proteins and lipids.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 10. Conclusion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
The mtDNA mutator mouse progeroid phenotype is a valid model of mammalian aging.
“However, the first strong experimental evidence demonstrating a causal relationship between aging and the accumulation of mtDNA mutations/deletions secondary to an exonuclease-deficient Pol γ was obtained with the creation of the mtDNA mutator mouse.”
The paper relies on this without support.
MtDNA typically exists as monomeric double-stranded, covalently closed circles.
“MtDNA typically exists as monomeric double-stranded, covalently closed circles.”
The paper relies on this without support.
The theory of mitohormesis states that low levels of ROS are important signaling molecules that regulate stress response pathways and enhance longevity.
“The theory of mitohormesis states that low levels of ROS are important signaling molecules that regulate stress response pathways and enhance longevity.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The oxidation of EF-Tu could lead to altered function and the incorrect translation of mitochondrial proteins, which include 13 components of the electron transport chain [78].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [78]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
“Of the handful of heterozygous mutations identified in POLG2, G451E (Longley et al., 2006) and R369G (Craig et al., 2012; Young et al., 2011) are linked to PEO.”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 6. Age-related mitochondrial diseases associated with defective mtDNA replication machinery > 6.2. PolG2
“Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G (Craig et al., 2012; Longley et al., 2006; Young et al., 2011).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > 9. Interventions to attenuate the symptoms of aging
“However, acute exercise in rats increased mRNA expression of Mnf1 and Mfn2 24 hours post-exercise (Cartoni et al., 2005).”
§ Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases > References
“23. Cartoni R Leger B Hock MB Praz M Crettenand A Pich S Ziltener JL Luthi F Deriaz O Zorzano A Gobelet C Kralli A Russell AP 2005 Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise The Journal of physiology 567 349 358 15961417 PMC1474174”
Citations
Cites
3 retracted
Safdar, A., Bourgeois, J. M., Ogborn, D. I., Little, J. P., Hettinga, B. P., Akhtar, M., Thompson, J. E., Melov, S., Mocellin, N. J., Kujoth, G. C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019581108 · Cited by 320
RetractedEndurance exercise is protective for mice with mitochondrial myopathy
Wenz, T., Diaz, F., Hernandez, D., & Moraes, C. T. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91571.2008 · Cited by 78
RetractedRETRACTED ARTICLE:Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice
Safdar, A., Khrapko, K., Flynn, J. M., Saleem, A., Lisio, M. D., Johnston, A. P. W., Kratysberg, Y., Samjoo, I. A., Kitaoka, Y., Ogborn, D. I., et al. (2015) · Skeletal Muscle · doi:10.1186/s13395-016-0075-9 · Cited by 68
RetractedAging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Parkinson's disease: clinical features and diagnosis
Jankovic, J. (2008) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2007.131045 · Cited by 5,720
Rapid evolution of animal mitochondrial DNA
Brown, W. M., George, M., & Wilson, A. C. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.4.1967 · Cited by 3,439
Oxidative DNA damage: mechanisms, mutation, and disease
Cooke, M. S., Evans, M. D., Dizdaroglu, M., & Lunec, J. (2003) · The FASEB Journal · doi:10.1096/fj.02-0752rev · Cited by 3,245
Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185
Mitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060
Cited by
Sorted by citations
Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases
Tan, B. L., Norhaizan, M. E., Liew, W.-P.-P., & Rahman, H. S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01162 · Cited by 1,221
“Numerous age-related diseases undergo the inflammation process, which is a risk factor in or partly of disease development (DeBalsi et al., 2017).”
BackgroundBrain aging and neurodegeneration: from a mitochondrial point of view
Grimm, A., & Eckert, A. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14037 · Cited by 565
“Implication of mitochondrial dynamics in aging DeBalsi and collaborators recently highlighted in a review that defects in the mtDNA replication machinery result in the accumulation of mutations, leading to decreased ETC. activity and impaired mitochondrial respiration (DeBalsi et al. 2016).”
BackgroundInflammaging and Oxidative Stress in Human Diseases: From Molecular Mechanisms to Novel Treatments
Zuo, L., Prather, E. R., Stetskiv, M., Garrison, D. E., Meade, J. R., Peace, T. I., & Zhou, T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184472 · Cited by 560
“Mitochondrial DNA (mtDNA) mutations can lead to increased ROS generation through disruptions of elec ron ansport chain [140].”
BackgroundMitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases
Giorgi, C., Marchi, S., Simões, I. C. M., Ren, Z., Morciano, G., Perrone, M., Patalas‐Krawczyk, P., Borchard, S., Jędrak, P., Pierzynowska, K., et al. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.006 · Cited by 484
PCR Based Determination of Mitochondrial DNA Copy Number in Multiple Species
Rooney, J. P., Ryde, I. T., Sanders, L. H., Howlett, E. H., Colton, M. D., Germ, K. E., Mayer, G. D., Greenamyre, J. T., & Meyer, J. N. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1875-1_3 · Cited by 441
Metadata
- Authors
- DeBalsi, K. L., Hoff, K. E., & Copeland, W. C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Copeland, William C.
- ORCID
- Copeland, William C.
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 33
- Pages
- 89-104
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC5086445
- OpenAlex
- W2344148285
- Semantic Scholar
- 8003ba7a002a2d21b3e89efa176e72ca5094b243
- Cited by
- 180
- References
- 276
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 15 · 2023: 13 · 2022: 24 · 2021: 31 · 2020: 29 · 2019: 14 · 2018: 18 · 2017: 14
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (Z01ES065078)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial DNA replication, mitochondrial dysfunction, aging, age-related diseases, reactive oxygen species, clonal expansion, mitochondrial dynamics, electron transport chain, cellular respiration
- MeSH terms
- Aging, DNA Replication, DNA, Mitochondrial, Humans, Mitochondria, Mutation, Mutagenesis, Reactive Oxygen Species, Genes, Mitochondrial
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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