The DOI matches its Crossref record; 273 of the 276 references it cites were found in a registry or an index; none of the 188 sources its claims cite is checked for support yet.
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
130 Not checked yet · 33 Own interpretation · 13 No basis given
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
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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
plain- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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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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
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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
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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
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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
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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
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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.
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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
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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.
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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
“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.
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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.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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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.
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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
“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.
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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
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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.
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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
“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
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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
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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
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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
“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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
None of the sources cited for this claim have been checked yet.
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
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.
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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.
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Probably not a substantial claim.
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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.
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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.
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It may state two separate claims as one.
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
- Not checked yetcites Nishiyama et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
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- 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”
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RetractedEndurance exercise is protective for mice with mitochondrial myopathy
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RetractedRETRACTED ARTICLE:Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice
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How mitochondria produce reactive oxygen species
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Parkinson's disease: clinical features and diagnosis
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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
The role of mitochondria in aging
Jang, J. Y., Blum, A., Liu, J., & Finkel, T. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120842 · Cited by 358
“Indeed, over 300 pathological mutations exist in human POLγ, and these mutations are linked to the development of a wide spectrum of conditions, including Parkinson’s disease and other age-related pathologies (58).”
BackgroundFunctional Mitochondria in Health and Disease
Herst, P. M., Rowe, M. R., Carson, G. M., & Berridge, M. V. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00296 · Cited by 332
“DeBalsi and colleagues propose that mistakes made by the mtDNA replication and repair machinery can also generate mtDNA mutations (68).”
BackgroundPleiotropic effects of mitochondria in aging
de Lima, T. I., Li, T. Y., Mottis, A., & Auwerx, J. H. (2022) · Nature Aging · doi:10.1038/s43587-022-00191-2 · Cited by 254
AMPK: Potential Therapeutic Target for Ischemic Stroke
Jiang, S., Li, T. X., Ji, T., Yi, W., Yang, Z. P., Wang, S., Yang, Y., & Gu, C. (2018) · Theranostics · doi:10.7150/thno.25674 · Cited by 256
“Mitochondrial dysfunction is the insufficiency and dysregulation of mitochondria, usually caused by harmful or extreme conditions, including cerebral ischemia and hypoxia [111, 112].”
BackgroundMitochondria in the signaling pathways that control longevity and health span
Akbari, M., Kirkwood, T. B. L., & Bohr, V. A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100940 · Cited by 234
“and all are components of the OXPHOS system, and are essential for mitochondrial function (DeBalsi et al., 2017).”
Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen, H., Deng, H., Li, B., Chen, J., Zhu, J., Zhang, X., Yoshida, S., & Zhou, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02044-3 · Cited by 284
Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease
Yan, X., Hu, Y., Wang, B., Wang, S., & Zhang, X. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.530219 · Cited by 230
Castelli, V., Benedetti, E., Antonosante, A., Catanesi, M., Pitari, G., Ippoliti, R., Cimini, A., & d’Angelo, M. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00132 · Cited by 224
“In a recent review, it has been highlighted that accumulation of mutations can induce an alteration in mtDNA replication, leading to electron transport chain activity loss and altered mitochondrial respiration (DeBalsi et al., 2017).”
BackgroundMitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection
Sas, K., Szabó, E., & Vécsei, L. (2018) · Molecules · doi:10.3390/molecules23010191 · Cited by 206
“Defects in the mtDNA replication mechanism and a failure in the repair of mtDNA might result in the accumulation of mutations, leading to mitochondrial dysfunction like decreased ETC enzyme activity and impaired cellular respiration [32].”
BackgroundChen, K., Lu, P., Beeraka, N. M., Sukocheva, O. A., Madhunapantula, S. V., Liu, J., Sinelnikov, M. Y., Nikolenko, V. N., Bulygin, K. V., Михалева, Л. М., et al. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.09.012 · Cited by 200
The Signaling of Cellular Senescence in Diabetic Nephropathy
Xiong, Y., & Zhou, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7495629 · Cited by 185
“In those mice, the accumulated mutations of mtDNA significantly accelerate aging phenotype [94].”
BackgroundFan, S., Tian, T., Chen, W., Lv, X., Lei, X., Zhang, H., Sun, S., Cai, L., Pan, G., He, L., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2505 · Cited by 154
“Frequent mutations have been reported in mitochondrial DNA(39), but we did not find any changed sequences in the miR-2392 target sites in CAL-27 and CAL27-re cell lines (Table S3).”
BackgroundGDF15 and Cardiac Cells: Current Concepts and New Insights
Rochette, L., Dogon, G., Zeller, M., Cottin, Y., & Vergely, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168889 · Cited by 158
“All of these proteins are components of the oxidative phosphorylation system and are essential for mitochondrial function [23].”
BackgroundProtective Role of Melatonin and Its Metabolites in Skin Aging
Bocheva, G., Slominski, R. M., Janjetović, Z., Kim, T., Böhm, M., Steinbrink, K., Reiter, R. J., Kleszczyński, K., & Slominski, A. T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031238 · Cited by 139
“Accum lating evidence supports a strong link between a d cline in mitochondrial quality and function and the aging process [71,72].”
BackgroundFragouli, E. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816561-4.00009-0 · Cited by 122
Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function
Singh, B., Schoeb, T. R., Bajpai, P., Slominski, A. T., & Singh, K. K. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0765-9 · Cited by 109
Li, H., Slone, J. D., Fei, L., & Huang, T. (2019) · Cells · doi:10.3390/cells8060608 · Cited by 106
“replication proteins—including Pol γ, PolG2, Twinkle, TFAM, MGME1, and RNase H1—lead to aging-related diseases [81].”
BackgroundNuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA
Rusecka, J. M., Kaliszewska, M., Bartnik, E., & Tońska, K. (2018) · Journal of Applied Genetics · doi:10.1007/s13353-017-0424-3 · Cited by 100
“…of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland 2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland processes rely on the nuclear genome (Tyynismaa et al. 2005; Capps et al. 2003; DeBalsi et al. 2016; Scheibye-Knudsen et al. 2015).”
Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging
Panov, A. V., & Dikalov, S. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/1323028 · Cited by 100
Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases
Nakagami, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/7469326 · Cited by 100
“The final common pathway in a variety of retinal diseases, including glaucoma and retinitis pigmentosa, is linked to retinal cellular death, and it is likely that ROS triggers cellular damage in these cases.”
BackgroundInfluentialMitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease
Butterfield, D. A., & Boyd-Kimball, D. (2020) · Antioxidants · doi:10.3390/antiox9090818 · Cited by 85
“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].”
BackgroundUltrasensitive deletion detection links mitochondrial DNA replication, disease, and aging
Lujan, S. A., Longley, M. J., Humble, M. H., Lavender, C. A., Burkholder, A., Blakely, E. L., Alston, C. L., Gorman, G. S., Turnbull, D. M., McFarland, R., et al. (2020) · Genome biology · doi:10.1186/s13059-020-02138-5 · Cited by 84
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Forensic transcriptome analysis using massively parallel sequencing
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“Inner membrane of mitochondrial structure consists of four ETC complexes along with ATP synthase leading to the synthesis of ATPmolecules (DeBalsi et al., 2017).”
BackgroundMitochondria: multifaceted regulators of aging
Son, J. M., & Lee, C. D. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.300 · Cited by 76
Mitochondrial Dysfunction in Aging and Cancer
Moro, L. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8111983 · Cited by 73
“gov/polg/), and they have been linked to several disorders, including age-related pathologies such as Parkinson’s disease [10,48,49].”
BackgroundInheritance through the cytoplasm
Camus, M. F., Alexander-Lawrie, B., Sharbrough, J., et al. (2022) · Heredity · doi:10.1038/s41437-022-00540-2 · Cited by 70
“2021), all of which have implications for mutation rate (Longley et al. 2005; DeBalsi et al. 2017; Wu et al. 2020).”
BackgroundMitochondrial DNA quality control in the female germline requires a unique programmed mitophagy
Palozzi, J. M., Jeedigunta, S. P., Minenkova, A. V., Monteiro, V., Thompson, Z. S., Lieber, T., & Hurd, T. R. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.10.005 · Cited by 67
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Lin, L., Yang, K., Zheng, L. P., Zhao, M., Sun, W., Zhu, Q., & Liu, S. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.05.033 · Cited by 69
Mitochondrial pathways in human health and aging
Bornstein, R., González, B., & Johnson, S. C. (2020) · Mitochondrion · doi:10.1016/j.mito.2020.07.007 · Cited by 71
“Accumulation of mtDNA mutations, particularly in the 13 mtDNA encoded ETC subunits, is thought to contribute to decreased respiratory function with age (85) (see “Polymorphisms and Heteroplasmy”).”
BackgroundPan, Y., Wang, N., Xia, P., Wang, E., Guo, Q., & Ye, Z. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.10.030 · Cited by 64
“8-hydroxyguanine DNA glycosylase (OGG1) and mitochondrial polymerase gamma (POLG) are the two most important repair enzymes of the mtDNA BER process (Luo et al., 2014; DeBalsi et al., 2017).”
Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease
Kumari, P., Sood, A., & Fernandes, V. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01147-7 · Cited by 68
The role of mitonuclear incompatibilities in allopatric speciation
Burton, R. S. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04059-3 · Cited by 70
“However, the spectrum of mtDNA mutations is not consistent with direct oxidative damage; rather that spectrum is more consistent with replication error potentially due to low fidelity of mitochondrial DNA polymerase (polymerase γ) [40].”
BackgroundIs There Still Any Role for Oxidative Stress in Mitochondrial DNA-Dependent Aging?
Zsurka, G., Peeva, V., Kotlyar, A. B., & Kunz, W. S. (2018) · Genes · doi:10.3390/genes9040175 · Cited by 60
“As an alternative explanation for the increased somatic mtDNA point mutation load in the aging process, the limitations in fidelity of POLG have been widely discussed [2,3,48].”
BackgroundTargeting Mitochondria to Counteract Age-Related Cellular Dysfunction
Madreiter‐Sokolowski, C. T., Sokolowski, A., Waldeck‐Weiermair, M., Malli, R., & Graier, W. F. (2018) · Genes · doi:10.3390/genes9030165 · Cited by 61
“The process of aging evokes various alterations in mitochondrial Ca2+ handling [17], mitochondrial respiration [80], mitochondrial structure [13], as well as in the mitochondrial genome [84], which are mutually interrelated to each other.”
BackgroundReplication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing
Billard, P., & Poncet, D. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194959 · Cited by 61
“In humans, pathologies generated by germline mutations in TFAM demonstrate MMF and clinical signs of ageing (cardiopathy, myopathy, diabetes, neurodegeneration) (for review, see [136]).”
BackgroundAge Dependent Dysfunction of Mitochondrial and ROS Metabolism Induced by Mitonuclear Mismatch
Pichaud, N., Bérubé, R., Côté, G., Belzile, C., Dufresne, F., Morrow, G., Tanguay, R. M., Rand, D. M., & Blier, P. U. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00130 · Cited by 57
“It is also believed that replication errors, such as deletion of mtDNA are a major force driving aging and age-related diseases (Bai and Wong, 2005; Clay Montier et al., 2009; Stumpf and Copeland, 2011; DeBalsi et al., 2017; Kauppila et al., 2017).”
BackgroundThe Role of Mitochondrial DNA Mutations in Cardiovascular Diseases
Dabravolski, S. A., Khotina, V. A., Sukhorukov, V. N., Kalmykov, V. A., Михалева, Л. М., & Orekhov, A. N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020952 · Cited by 56
“Secondly, the mitochondrial DNA repair system is not so efficient in comparison to the nuclear one [32].”
BackgroundComplex II ambiguities—FADH2 in the electron transfer system
Gnaiger, E. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105470 · Cited by 55
Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression
Pérez-Amado, C. J., Bazan-Cordoba, A., Hidalgo‐Miranda, A., & Jiménez‐Morales, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147369 · Cited by 54
MRE11-Dependent Instability in Mitochondrial DNA Fork Protection Activates cGAS Inflammation
Luzwick, J. W., Dombi, E., Boisvert, R. A., Roy, S., Park, S., Kunnimalaiyaan, S., Goffart, S., Schindler, D., & Schlacher, K. (2020) · Science Advances · doi:10.1126/sciadv.abf9441 · Cited by 50
“Mutations in mitochondrial replisome components cause mitochondrial disease, and mtDNA instability causes diverse physiological manifestations including premature aging, abnormal cellular energetics, and developmental abnormalities (3).”
BackgroundMitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes
Kobayashi, H., & Imanaka, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313144 · Cited by 51
“These factors include ultraviolet radiation, chemical toxins (pollutants, pesticides, tobacco smoke, and iron), radiation exposure, drugs and pharmaceuticals (chemotherapeutic agents, antibiotics, and endocrine-disrupting chemicals), and dietary and lifestyle factors (poor diet and alcohol…”
Mitonuclear genomics and aging
Reynolds, J. C., Bwiza, C. P., & Lee, C. D. (2020) · Human Genetics · doi:10.1007/s00439-020-02119-5 · Cited by 56
Guo, K., & Lü, Y. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1388759 · Cited by 47
The Interaction of Diet and Mitochondrial Dysfunction in Aging and Cognition
Kaliszewska, A., Allison, J., Martini, M., & Arias, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073574 · Cited by 52
The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity
Chaudhari, S. N., & Kipreos, E. T. (2018) · BioEssays · doi:10.1002/bies.201800005 · Cited by 42
Wei, Y., Sun, L., Liu, C., & Li, L. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02390-z · Cited by 40
Disentangling the intertwined roles of mutation, selection and drift in the mitochondrial genome
Schaack, S., Ho, E. K. H., & Macrae, F. (2019) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2019.0173 · Cited by 38
Hu, Q., Ren, J., Wu, J., Li, G., Wu, X., Liu, S., Wang, G., Gu, G., & Li, J. (2017) · Surgical Infections · doi:10.1089/sur.2016.276 · Cited by 39
“In addition, a series of studies demonstrated that mtDNA could be recognized by pattern recognition receptors and triggered immune inflammatory responses [11–13].”
Role of microRNAs in neurodegeneration induced by environmental neurotoxicants and aging
Singh, T., & Yadav, S. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101068 · Cited by 41
Mitochondria, its DNA and telomeres in ageing and human population
Zole, E., & Ranka, R. (2018) · Biogerontology · doi:10.1007/s10522-018-9748-6 · Cited by 36
“…with a normal ageing process in several studies and have been proposed either as a useful marker of natural ageing in human subjects or as a factor affecting human longevity (Cortopassi et al. 1992; Meissner et al. 1997; Linnane et al. 1989; Raule et al. 2014; reviewed in DeBalsi et al. 2017).”
BackgroundLin, L., Zhu, Q., Zheng, L. P., Zhao, M., Fan, J., & Liu, S. (2020) · Journal of Functional Foods · doi:10.1016/j.jff.2020.103954 · Cited by 38
Chen, F., Liu, X., Zhao, J., Xie, B., Qian, J., Liu, W., Li, B., Zhang, X., Huijuan, W., & Yan, J. (2020) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2020.102300 · Cited by 37
PCR-Based Determination of Mitochondrial DNA Copy Number in Multiple Species
Leuthner, T. C., Hartman, J. H., Ryde, I. T., & Meyer, J. N. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1433-4_8 · Cited by 32
Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing
Hedberg‐Oldfors, C., Lindgren, U., Basu, S., Visuttijai, K., Lindberg, C., Falkenberg, M., Larsson, E., & Oldfors, A. (2020) · Brain Pathology · doi:10.1111/bpa.12931 · Cited by 35
“This is caused by defects in proteins involved in mtDNA maintenance and results in COX deficiency in muscle fiber segments (19,26).”
BackgroundmtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases
Shang, D., Huang, M., Wang, B., Yan, X., Wu, Z., & Zhang, X. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220810114644 · Cited by 44
“In somatic cells, the levels of mutated mtDNA increase with age [37], and the most common causes of mtDNA mutations are, an error in mtDNA replication [38, 39] and an accumulation of oxidative damage [40, 41].”
Intimate Relations—Mitochondria and Ageing
Webb, M., & Sideris, D. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207580 · Cited by 36
Spano, L., Étain, B., Meyrel, M., Hennion, V., Gross, G., Laplanche, J., Bellivier, F., & Cynthia Marie-claire, A. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01891-4 · Cited by 40
“This leads to a decrease of mtDNAcn that therefore negatively correlates with age [14].”
BackgroundCormio, A., Sanguedolce, F., Musicco, C., Pesce, V., Calò, G., Bufo, P., Carrieri, G., & Cormio, L. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.07.001 · Cited by 33
Xue, C., Li, G., Bao, Z., Zhou, Z., & Lan-juan, L. (2021) · Cancer Cell International · doi:10.1186/s12935-021-01996-8 · Cited by 32
Kaur, P., Longley, M. J., Pan, H., Wang, H., & Copeland, W. C. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky875 · Cited by 32
“Consequently, defects in mtDNA replication are a principle cause of severe and heritable metabolic disorders classified as mitochondrial diseases (9,10).”
Self-citationAbdullaev, S. A., Gubina, N., Bulanova, T., & Gaziev, A. I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041196 · Cited by 34
“It has been demonstrated in different studies, that ionizing radiation induces mutations and specific deletions in mtDNA in cells (in vitro) and rodent tissues (in vivo) [15,16].”
BackgroundInfluentialSchwartzman, J. D., McCall, M., Ghattas, Y. S., Pugazhendhi, A. S., Wei, F., Ngo, C., Ruiz, J., Seal, S., & Coathup, M. J. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122683 · Cited by 34
Inherited mitochondrial genomic instability and chemical exposures
Chan, S. S. L. (2017) · Toxicology · doi:10.1016/j.tox.2017.07.014 · Cited by 26
“Much of what is known of the biochemistry and cell biology of proteins with mutations causing mtDNA diseases have been excellently summarized in recent reviews by the Copeland group (DeBalsi et al. 2017; Stumpf and Copeland 2014; Young and Copeland 2016).”
BackgroundMitochondrial DNA Mutagenesis: Feature of and Biomarker for Environmental Exposures and Aging
Leuthner, T. C., & Meyer, J. N. (2021) · Current Environmental Health Reports · doi:10.1007/s40572-021-00329-1 · Cited by 32
Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases
Morciano, G., Boncompagni, C., Ramaccini, D., Pedriali, G., Bouhamida, E., Tremoli, E., Giorgi, C., & Pinton, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043414 · Cited by 29
“However, mutations in mtDNA are more frequent than in the nuclear genome; this may be highlighted by the fact that mtDNA is more exposed to detrimental agents, unprotected by the histones, minimal DNA repair and that the mtDNA mutations are caused mostly by uncontrolled ROS formation which generates oxidative stress […”
The conservation utility of mitochondrial genetic diversity in macrogenetic research
Schmidt, C., & Garroway, C. J. (2021) · Conservation Genetics · doi:10.1007/s10592-021-01333-6 · Cited by 29
Therapeutic Antiaging Strategies
Mishra, S. K., Balendra, V., Esposto, J., Obaid, A. A., Maccioni, R. B., Jha, N. K., Perry, G. L., Moustafa, M., Al-Shehri, M., Singh, M. P., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10102515 · Cited by 34
Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?
Grimm, A. (2021) · Cells · doi:10.3390/cells10102531 · Cited by 26
“Evidence shows that the accumulation of mtDNA mutations over time is a central mechanism driving aging and age-related diseases, as they may lead to decreased ETC activity and impaired mitochondrial respiration [1,18].”
BackgroundDynamic features of human mitochondrial DNA maintenance and transcription
Akbari, M., Nilsen, H. L., & Montaldo, N. P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.984245 · Cited by 27
Mitochondria: a new intervention target for tumor invasion and metastasis
Zhou, Q., Cao, T., Li, F., Zhang, M., Li, X., Zhao, H., & Zhou, Y. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00899-4 · Cited by 26
Lee, L., Chou, W., Chen, W.-P., Wang, M.-F., Chen, Y., Chen, C., & Tung, K. (2021) · Nutrients · doi:10.3390/nu13103659 · Cited by 26
“8-hydroxy-2’-deoxyguanosine (8-OHdG) is an indicator of mitochondrial DNA damage [22].”
BackgroundOvarian Aging: Mechanisms, Age‐Related Disorders, and Therapeutic Interventions
Liu, X., Zhao, Y., Feng, Y., Wang, S., & Zhang, J. (2025) · MedComm · doi:10.1002/mco2.70481 · Cited by 34
Targeting immunosenescence for improved tumor immunotherapy
Liu, Z., Zuo, L., Zhou, Z., Liu, S., Ba, Y., Zuo, A., Ren, Y., Zhang, C., Chen, Y., Ma, H., et al. (2024) · MedComm · doi:10.1002/mco2.777 · Cited by 24
Zhao, X.-Y., Yang, A., Fu, Y., et al. (2020) · Environmental Pollution · doi:10.1016/j.envpol.2020.114026 · Cited by 19
Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging
Akbari, M., Shanley, D. P., Bohr, V. A., & Rasmussen, L. J. (2021) · Cells · doi:10.3390/cells10123544 · Cited by 25
“Accumulation of various forms of mtDNA damage correlates with aging and age-related diseases [60].”
BackgroundMelvin, R. G., & Ballard, J. W. O. (2017) · Mutagenesis · doi:10.1093/mutage/gex004 · Cited by 24
“(73) and Young and Copeland (74) have recently reviewed the role of the mtDNA replication machinery in mutagenesis and age-related disease.”
Hypothesized Evolutionary Consequences of the Alternative Oxidase (AOX) in Animal Mitochondria
Weaver, R. J. (2019) · Integrative and Comparative Biology · doi:10.1093/icb/icz015 · Cited by 23
Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations
DeBalsi, K. L., Longley, M. J., Hoff, K. E., & Copeland, W. C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.773341 · Cited by 22
Self-citationde la Lastra, J. M. P., Andrés, C., Plou, F. J., & Pérez‐Lebeña, E. (2021) · Processes · doi:10.3390/pr9030506 · Cited by 22
Oexner, R. R., Pla‐Martín, D., Paß, T., Wiesen, M. H. J., Zentis, P., Schauss, A. C., Baris, O. R., Kimoloi, S., & Wiesner, R. J. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.12.14 · Cited by 19
“37,38 It is thus possible that type IIB fibers inherently have higher mtDNA replication error rates compared to other fiber types, which become exacerbated in the presence of a defective Twinkle as observed in our model.”
Brooks, N. A. H., Riar, I., & Klegeris, A. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-01459 · Cited by 23
“Moreover, transgenic mice overexpressing human TFAM are protected from memory impairment and cardiac damage following experimental myocardial infarction compared to wild-type animals (DeBalsi et al., 2017).”
Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias
Waneka, G., Svendsen, J. M., Havird, J. C., & Sloan, D. B. (2021) · Genetics · doi:10.1093/genetics/iyab116 · Cited by 19
Genetic perspective of uniparental mitochondrial DNA landscape on the Punjabi population, Pakistan
Bhatti, S., Abbas, S., Aslamkhan, M., Attimonelli, M., Trinidad, M. S., Aydın, H. H., de Souza, É. M. S., & Gonzalez, G. R. (2017) · Mitochondrial DNA Part A · doi:10.1080/24701394.2017.1350951 · Cited by 17
“Despite these elaborative findings, mitochondrial DNA is also a key player that subsequently orchestrates the biological underpinning in evolutionary genetics, forensic sciences and molecular ecology (DeBalsi et al. 2017).”
BackgroundBusnelli, A., Navarra, A., & Levi-Setti, P. E. (2021) · Antioxidants · doi:10.3390/antiox10010055 · Cited by 16
Abdullaev, S. A., Glukhov, S. I., & Gaziev, A. I. (2021) · Antioxidants · doi:10.3390/antiox10121885 · Cited by 24
“H2O2 molecules are the most stable and capable of migrating over long distances (1 μm or more) [34,35].”
BackgroundUnraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease
Fang, S., Jiang, M., Jiao, J., Zhao, H., Liu, D., Gao, D., Wang, T., Yang, Z. X., & Yuan, H. (2025) · Aging and Disease · doi:10.14336/ad.2024.1253 · Cited by 18
“8-OxodG mutations are prevalent in the mutated p53 gene, confirming the link between oxidative stress and cancer [129]. mtDNA mutations result in upregulated ROS generation by disrupting the electron transport chain [130].”
An Ecologist’s Guide to Mitochondrial DNA Mutations and Senescence
Hood, W. R., Williams, A. S., & Hill, G. E. (2019) · Integrative and Comparative Biology · doi:10.1093/icb/icz097 · Cited by 15
Antimutagenic Activity as a Criterion of Potential Probiotic Properties
Prazdnova, E. V., Mazanko, M. S., Chistyakov, V. A., Bogdanova, A. A., Refeld, A. G., Kharchenko, E. Y., & Chikindas, M. L. (2022) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-021-09870-9 · Cited by 15
Nian, S., Mi, Y., Ren, K., Wang, S., Li, M., & Yang, D. (2022) · Human Cell · doi:10.1007/s13577-022-00703-7 · Cited by 15
Toh, Y. L., Wong, E., Chae, J., Yap, N. Y., Yeo, A. H. L., Shwe, M., & Chan, A. (2020) · Mitochondrion · doi:10.1016/j.mito.2020.07.004 · Cited by 15
Liver X receptors and the hallmarks of aging: From molecular mechanisms to therapeutic opportunities
Poirot, M., Buñay, J., Ayadi, S., Silvente‐Poirot, S., & de Médina, P. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102967 · Cited by 20
“Aging is associated with reduced mitochondrial mass, altered dynamics, accumulation of mtDNA mutations, and impaired respiratory chain efficiency (DeBalsi et al., 2017; Gonzalez-Freire et al., 2015).”
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
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