New insights into the role of mitochondria in aging: mitochondrial dynamics and more

May combine two claims.

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders.

“A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders.”

May combine two claims.

Genetic defects in the proteins involved in mitochondrial fusion and fission lead to severely altered mitochondrial shape, loss of mtDNA integrity, increased oxidative stress and apoptotic cell death; these alterations can subsequently cause developmental abnormality, neuromuscular degeneration and metabolic disorders in humans.

“genetic defects in the proteins involved in mitochondrial fusion and fission lead to severely altered mitochondrial shape, loss of mtDNA integrity, increased oxidative stress and apoptotic cell death; it has been shown that these alterations can subsequently cause developmental abnormality, neuromuscular degeneration and metabolic disorders in humans (Chen and Chan, 2009).”

• cites Chen and Chan, 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Drp1 is predominantly located in the cytosol and is recruited to mitochondrial surfaces, where it associates with Fis1 and assembles into foci that serve as potential scission sites for future fission events.

“Drp1, a member of the dynamin family of large GTPases, is predominantely located in the cytosol and is recruited to mitochondrial surfaces, where it associates with Fis1 and assembles into foci that serve as potential scission sites for future fission events (Smirnova et al., 2001).”

• cites Smirnova et al., 2001Not checked yet

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Repression of Mfn2 in cells decreases oxygen consumption, glucose oxidation, mitochondrial membrane potential and the expression of oxidative phosphorylation proteins.

“Repression of Mfn2 in cells decreases oxygen consumption, glucose oxidation, mitochondrial membrane potential and the expression of oxidative phosphorylation proteins (Bach et al., 2003; Chen et al., 2005; Pich et al., 2005).”

• cites Bach et al., 2003 sourceNot checked yet

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• cites Chen et al., 2005 sourceNot checked yet

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• cites Pich et al., 2005Not checked yet

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The capacity for mitochondrial biogenesis diminishes with age and this is an important parameter in the mitochondrial dysfunction associated with aging.

“The capacity for mitochondrial biogenesis diminishes with age and this is an important parameter in the mitochondrial dysfunction associated with aging (Fannin et al., 1999; Sugiyama et al., 1993).”

• cites Fannin et al., 1999Not checked yet

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• cites Sugiyama et al., 1993Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Mfn2 is highly abundant in heart and skeletal muscle and is expressed at low levels in numerous other human tissues.

“Although both proteins are widely expressed, Mfn2 is highly abundant in heart and skeletal muscle and is reportedly expressed at low levels in numerous other human tissues (Bach et al., 2003; Santel et al., 2003).”

• cites Bach et al., 2003 sourceNot checked yet

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• cites Santel et al., 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Fis1 overexpression in cultured cells results in mitochondrial fragmentation and depletion of Fis1 leads to elongated mitochondria.

“Fis1 overexpression in cultured cells results in mitochondrial fragmentation and depletion of Fis1 leads to elongated mitochondria (Yoon et al., 2003).”

• cites Yoon et al., 2003Not checked yet

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May combine two claims.

Dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process.

“Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Levels of Opa1 activity are controlled by proteolytic cleavage; a decrease in the amount of long or short isoforms is important in the regulation of cell death mediated by fragmented mitochondria.

“levels of Opa1 activity are also controlled by proteolytic cleavage; a decrease in the amount of long or short isoforms, for example, has been shown to be important in the regulation of cell death mediated by fragmented mitochondria (Arnoult et al., 2005a; Duvezin-Caubet et al., 2006).”

• cites Arnoult et al., 2005aNot checked yet

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• cites Duvezin-Caubet et al., 2006Not checked yet

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The accumulation of aging-associated mutations and deletions in mitochondrial DNA (mtDNA) can impair the function of the respiratory chain and enhance ROS production.

“the accumulation of aging-associated mutations and deletions in mitochondrial DNA (mtDNA) can impair the function of the respiratory chain and enhance ROS production (Chomyn and Attardi, 2003; Harman, 1972).”

• cites Chomyn and Attardi, 2003Not checked yet

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• cites Harman, 1972Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The free-radical theory of aging proposes that cumulative damage to biological macromolecules by oxygen radicals (ROS) leads to irreversible cell damage and an overall functional decline.

“This theory proposes that cumulative damage to biological macromolecules by oxygen radicals (reactive oxygen species; ROS) leads to irreversible cell damage and an overall functional decline (Harman, 1956).”

• cites Harman, 1956 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Mitochondrial fusion involves multiple steps, including mitochondrial tethering and fusion of MOMs, docking and fusion of the mitochondrial inner membranes (MIMs) and mixing of intramitochondrial components.

“Mitochondrial fusion involves multiple steps, including mitochondrial tethering and fusion of MOMs, docking and fusion of the mitochondrial inner membranes (MIMs) and mixing of intramitochondrial components (Ishihara et al., 2004).”

• cites Ishihara et al., 2004 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Drp1 activity is post-translationally modified, allowing complex intracellular signaling pathways to regulate mitochondrial morphology by modulating Drp1 activity.

“The finding that Drp1 activity is post-translationally modified (e.g. by phosphorylation, ubiquitylation and sumoylation) revealed another level of cellular control whereby complex intracellular signaling pathways can regulate mitochondrial morphology during altered states of mitochondrial function by modulating the activity of Drp1 (Wasilewski and Scorrano, 2009).”

• cites Wasilewski and Scorrano, 2009Not checked yet

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May combine two claims.

Inhibition of Drp1 activity transforms wild-type mitochondria into long and interconnected organelles, whereas overexpression of Drp1 results in mitochondrial fragmentation.

“when Drp1 activity is inhibited, wild-type mitochondria are transformed into long and interconnected organelles (Pitts et al., 1999) and, conversely, overexpression of Drp1 in cells results in mitochondrial fragmentation (Arnoult et al., 2005b).”

• cites Pitts et al., 1999Not checked yet

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• cites Arnoult et al., 2005bNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Opa1 plays a constitutive role in MIM fusion and remodeling of mitochondrial cristae structure.

“Opa1 is believed to play a constitutive role in MIM fusion and remodeling of mitochondrial cristae structure (Frezza et al., 2006).”

• cites Frezza et al., 2006 sourceNot checked yet

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Decreased fusion can result in mitochondrial fragmentation because of excessive fission, whereas decreased fission can generate long and highly interconnected mitochondria.

“Whereas decreased fusion can result in mitochondrial fragmentation because of excessive fission, decreased fission can generate long and highly interconnected mitochondria (Sesaki and Jensen, 1999).”

• cites Sesaki and Jensen, 1999Not checked yet

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These mtDNA-mutator mice had a shorter life span and displayed age-related phenotypes at an early age.

“These mtDNA-mutator mice, with accelerated levels of mutations, had a shorter life span and displayed age-related phenotypes [such as hair loss, kyphosis (curvature of the spine), osteoporosis and sarcopenia] at an early age (Kujoth et al., 2005; Trifunovic et al., 2004).”

• cites Kujoth et al., 2005 sourceNot checked yet

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• cites Trifunovic et al., 2004 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The role of Fis1 in mitochondrial fission is primarily to act as an anchor protein for Drp1.

“The role of Fis1 in mitochondrial fission is primarily to act as an anchor protein for Drp1 (Wasilewski and Scorrano, 2009).”

• cites Wasilewski and Scorrano, 2009Not checked yet

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May combine two claims.

These changes were not accompanied by increased levels of oxidative stress, a finding that has also been confirmed in humans.

“Interestingly, these changes were not accompanied by increased levels of oxidative stress, a finding that has also been confirmed in humans (Hutter et al., 2007).”

• cites Hutter et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A functional decline in mitochondria occurs with age and properly functioning mitochondria are crucial for longevity and minimizing age-related diseases.

“the fact that a functional decline in mitochondria occurs with age and that properly functioning mitochondria are crucial for longevity and minimizing age-related diseases cannot be refuted.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Both Mfn proteins mediate fusion through their active GTPase domains by tethering opposing mitochondrial membranes.

“Both Mfn proteins mediate fusion through their active GTPase domains by tethering opposing mitochondrial membranes (Chen et al., 2003; Eura et al., 2003).”

• cites Chen et al., 2003 sourceNot checked yet

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• cites Eura et al., 2003Not checked yet

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Classified as probably not a substantial claim. May combine two claims.

The exchange of mitochondrial contents by mitochondrial fusion enables the complementation of pathogenic (mutant) mtDNA in heteroplasmic cells, as introducing wild-type mtDNA dilutes the mutant mtDNA molecules and prevents them from reaching a crucial threshold in the cell.

“It has been suggested that the exchange of mitochondrial contents by mitochondrial fusion enables the complementation of pathogenic (mutant) mtDNA in heteroplasmic cells, as introducing wild-type mtDNA dilutes the mutant mtDNA molecules and prevents them from reaching a crucial threshold in the cell (Chen et al., 2007; Sato et al., 2006; Sato et al., 2009).”

• cites Chen et al., 2007Not checked yet

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• cites Sato et al., 2006Not checked yet

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• cites Sato et al., 2009Not checked yet

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May combine two claims.

The fragmentation of mitochondria is a prerequisite for autophagy, and smaller mitochondria might be autophagocytosed more easily than larger ones and require less energy.

“The fragmentation of mitochondria is a prerequisite for autophagy (Twig et al., 2008), which might be physiologically favorable: smaller mitochondria might be autophagocytosed more easily than larger ones and require less energy.”

• cites Twig et al., 2008 sourceNot checked yet

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Defects in yeast Fzo1p and Mgm1p result in slow growth on rich medium and a loss of mtDNA.

“This was originally reported in yeast studies, in which defects in Fzo1p and Mgm1p (orthologs of mammalian Mfns and Opa1, respectively) were observed to result in slow growth on rich medium and a loss of mtDNA (Hermann et al., 1998; Rapaport et al., 1998).”

• cites Hermann et al., 1998Not checked yet

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• cites Rapaport et al., 1998Not checked yet

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May combine two claims.

In response to oxidant-induced damage, mitochondrial fission generates daughter mitochondria with different Δψm, whereby mitochondria with a lower Δψm can be targeted for degradation by autophagy, whereas parent mitochondria remain intact.

“Intriguingly, in response to oxidant-induced damage, mitochondrial fission generates daughter mitochondria with different Δψm, whereby mitochondria with a lower Δψm can be targeted for degradation by autophagy, whereas parent mitochondria remain intact (Gomes and Scorrano, 2008; Twig et al., 2008).”

• cites Gomes and Scorrano, 2008Not checked yet

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• cites Twig et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

MOMP and remodeling of mitochondrial membranes permit the release of apoptogenic factors such as cytochrome c and AIF from the intermembrane space into the cytosol.

“A key event in this process involves mitochondrial outer membrane permeabilization (MOMP) and the remodeling of mitochondrial membranes, permitting the release of apoptogenic factors such as cytochrome c (Liu et al., 1996) and apoptosis-inducing factor (AIF) (Susin et al., 1999) from the intermembrane space into the cytosol (Kroemer et al., 2007).”

• cites Liu et al., 1996 sourceNot checked yet

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• cites Susin et al., 1999Not checked yet

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• cites Kroemer et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Apoptogenic factors released from mitochondria initiate apoptosis through caspase-dependent or -independent pathways.

“These apoptogenic factors can then initiate apoptosis through caspase-dependent or -independent pathways (Green and Kroemer, 2004).”

• cites Green and Kroemer, 2004Not checked yet

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May combine two claims.

Alterations in the expression levels of both fusion and fission proteins can influence the mitotic segregation of mutant and wild-type mtDNA, and might be an important factor in the proliferation of dysfunctional mitochondria observed with aging and mitochondrial disease.

“Therefore, alterations in the expression levels of both fusion and fission proteins can influence the mitotic segregation of mutant and wild-type mtDNA, and might be an important factor in the proliferation of dysfunctional mitochondria that is observed with aging and mitochondrial disease.”

May combine two claims.

Repression of Fis1 activity causes prolonged mitochondrial elongation (fusion) and senescence-related phenotypes, whereas overexpressed Fis1 inhibits senescence.

“Repression of Fis1 activity has been shown to cause prolonged mitochondrial elongation (fusion) and senescence-related phenotypes [i.e. reduced mitochondrial membrane potential (Δψm) and increased levels of ROS], whereas overexpressed Fis1 inhibits senescence (Lee et al., 2007; Yoon et al., 2006).”

• cites Lee et al., 2007Not checked yet

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• cites Yoon et al., 2006Not checked yet

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The presence of abnormal mitochondria in models of replicative senescence and in aging animals is associated with an overall shift towards more fusion events, resulting mainly from the downregulation of fission proteins and reduced clearance of mitochondria by autophagy.

“This is corroborated by studies conducted both in models of replicative senescence and in aging animals, in which the presence of abnormal mitochondria was associated with an overall shift towards more fusion events, which resulted mainly from the downregulation of fission proteins and reduced clearance of mitochondria by autophagy (Lee et al., 2007; Yoon et al., 2006).”

• cites Lee et al., 2007Not checked yet

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• cites Yoon et al., 2006Not checked yet

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Loss of mitochondrial fusion in skeletal muscle results in increased mtDNA point mutations and deletions as well as severe mtDNA depletion, which preceded the phenotypic changes observed in these mutant mice.

“Furthermore, loss of mitochondrial fusion in skeletal muscle resulted in increased mtDNA point mutations and deletions as well as severe mtDNA depletion, which preceded the phenotypic changes observed in these mutant mice.”

• cites Chen et al., 2010 sourceNot checked yet

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May combine two claims.

In healthy cells, fission might prevent the sustained elongation of mitochondria that can induce cellular senescence, in part through autophagy and the selective clearance of damaged organelles.

“Therefore, in healthy cells, fission might prevent the sustained elongation of mitochondria that can induce cellular senescence. It does this in part through autophagy and the selective clearance of damaged organelles.”

May combine two claims.

The selective degradation of damaged mitochondria (mitophagy) has been shown in fibroblasts from patients harboring mtDNA mutations, with a greater than normal autophagic response compared with control cells.

“The selective degradation of damaged mitochondria (also known as mitophagy) has been shown in fibroblasts from patients harboring mtDNA mutations. A greater than normal autophagic response has been observed in these patient cells compared with control cells (James et al., 1996).”

• cites James et al., 1996Not checked yet

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Reduced AMPK activity has been reported in aged animals and is directly linked to age-related insulin resistance and impaired fatty-acid oxidation.

“Reduced AMPK activity has been reported in aged animals and is directly linked to age-related insulin resistance and impaired fatty-acid oxidation (Qiang et al., 2007; Reznick et al., 2007).”

• cites Qiang et al., 2007Not checked yet

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• cites Reznick et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Mitochondria play a crucial role in mediating apoptosis.

“It is well known that mitochondria play a crucial role in mediating apoptosis (Green, 1998).”

• cites Green, 1998Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Mutations in mtDNA accumulate over time and must reach a crucial threshold (~70-90% of total mtDNA) before associated clinical symptoms manifest.

“Mutations in mtDNA accumulate over time and must reach a crucial threshold (~70-90% of total mtDNA) before associated clinical symptoms manifest (Wallace and Fan, 2009).”

• cites Wallace and Fan, 2009Not checked yet

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May combine two claims.

Muscle-specific Mfn1- and Mfn2-knockout mice have impaired mitochondrial function, abnormal mitochondrial proliferation and muscle loss.

“In a recent study conducted by Chen et al., muscle-specific Mfn1- and Mfn2-knockout mice were reported to have impaired mitochondrial function, abnormal mitochondrial proliferation and muscle loss (Chen et al., 2010).”

• cites Chen et al., 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

These mitochondrial adaptations seem to be driven by a regulatory pathway that involves PGC-1α, ERRα and Mfn2, and can be activated by several physiological stimuli, including exercise and calorie restriction.

“These mitochondrial adaptations seem to be driven by a regulatory pathway that involves PGC-1α, ERRα and Mfn2, and can be activated by several physiological stimuli, including exercise and calorie restriction.”

May combine two claims.

Proper mitochondrial dynamics are important for the accurate segregation and transmission of mtDNA during mitosis, and there is a relationship between mitochondrial dynamics and genomic stability.

“Proper mitochondrial dynamics are important for the accurate segregation and transmission of mtDNA during mitosis, and numerous studies have shown that there is a relationship between mitochondrial dynamics and genomic stability.”

May combine two claims.

Reduced lysosomal degradation capacity and autophagy have been reported in aged hepatocytes and in skeletal muscle from aged Fischer 344 rats.

“Indeed, reduced lysosomal degradation capacity and autophagy have been reported in aged hepatocytes (Donati et al., 2001; Terman, 1995) and, more recently, have been observed in skeletal muscle from aged Fischer 344 rats (Wohlgemuth et al., 2010).”

• cites Donati et al., 2001Not checked yet

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• cites Terman, 1995Not checked yet

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• cites Wohlgemuth et al., 2010 sourceNot checked yet

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Regulated degradation of mitochondria is intimately linked to mitochondrial fission and is particularly important for long-lived post-mitotic cells that possess a low regenerative capacity and experience high levels of oxidative damage.

“Regulated degradation of mitochondria is intimately linked to mitochondrial fission (Narendra et al., 2008) and is particularly important for long-lived post-mitotic cells that possess a low regenerative capacity and experience high levels of oxidative damage.”

• cites Narendra et al., 2008 sourceNot checked yet

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Mitochondrial fusion through intramitochondrial exchange increases the tolerance of a cell to mutant mtDNA and protects the integrity of the mitochondrial genome.

“This study supports the hypothesis that mitochondrial fusion through intramitochondrial exchange increases the tolerance of a cell to mutant mtDNA and protects the integrity of the mitochondrial genome.”

• cites Chen et al., 2010 sourceNot checked yet

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May combine two claims.

Depletion of Drp1 in HeLa cells results in mitochondrial dysfunction owing to a loss of mtDNA, suggesting that Drp1 is important for mitochondrial inheritance during cell division and for mitochondrial function.

“Interestingly, depletion of Drp1 in HeLa cells also results in mitochondrial dysfunction owing to a loss of mtDNA, suggesting that Drp1 is also important for mitochondrial inheritance during cell division, as well as for mitochondrial function (Parone et al., 2008).”

• cites Parone et al., 2008 sourceNot checked yet

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Aged tissues are highly susceptible to increased oxidative stress and have a high incidence of apoptosis.

“This is because aged tissues are highly susceptible to increased oxidative stress and have a high incidence of apoptosis (Dirks and Leeuwenburgh, 2005; Dupont-Versteegden, 2005; Seo et al., 2008).”

• cites Dirks and Leeuwenburgh, 2005Not checked yet

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• cites Dupont-Versteegden, 2005Not checked yet

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• cites Seo et al., 2008Not checked yet

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The role of Drp1 as a pro-fission and pro-apoptotic protein is dependent on its stable association with the MOM and is governed by Bax and/or Bak sumoylation and other post-translational modifications.

“The role of Drp1 as a pro-fission and pro-apoptotic protein is dependent on its stable association with the MOM and is governed by Bax and/or Bak sumoylation (Wasiak et al., 2007) and other post-translational modifications (Chang and Blackstone, 2007; Cribbs and Strack, 2007).”

• cites Wasiak et al., 2007Not checked yet

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• cites Chang and Blackstone, 2007Not checked yet

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• cites Cribbs and Strack, 2007Not checked yet

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Knockdown of Opa1 expression with siRNA results in increased mitochondrial fission and decreased Δψm in HeLa cells, leading to abnormal mitochondrial cristae, mitochondrial fragmentation and the release of cytochrome c.

“Knockdown of Opa1 expression with small interfering RNA (siRNA) results in increased mitochondrial fission and decreased Δψm in HeLa cells, leading to abnormal mitochondrial cristae, mitochondrial fragmentation and the release of cytochrome c (Olichon et al., 2003).”

• cites Olichon et al., 2003 sourceNot checked yet

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Similar findings for S-nitrosylated Drp1 were reported in the brain tissue of AD patients, further supporting the involvement of increased mitochondrial fission events in the pathogenesis of AD.

“Similar findings for S-nitrosylated Drp1 were reported in the brain tissue of AD patients, further supporting the involvement of increased mitochondrial fission events in the pathogenesis of AD (Cho et al., 2009).”

• cites Cho et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

mtHtt affects mitochondrial fusion and fission events by colocalizing with Drp1 at specific fission sites on the MOM.

“It was recently suggested that mtHtt affects mitochondrial fusion and fission events by colocalizing with Drp1 at specific fission sites on the MOM (Bossy-Wetzel et al., 2008).”

• cites Bossy-Wetzel et al., 2008Not checked yet

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• AssumptionRests on an assumption: Huntington's disease is caused by a mutation in the huntingtin gene (HTT).

May combine two claims.

Accumulation of Aβ-containing plaques derived from APP causes cellular toxicity, mitochondrial dysfunction and aberrant mitochondrial structure, which contribute to the pathogenesis of AD.

“Accumulation of β-amyloid (Aβ)-containing plaques derived from the amyloid precursor protein (APP) causes cellular toxicity, mitochondrial dysfunction and aberrant mitochondrial structure, which contribute to the pathogenesis of AD.”

• cites Wang et al., 2008Not checked yet

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• cites Cho et al., 2009Not checked yet

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Although the roles of fission proteins in mitochondrial dynamics and cell death are closely associated, they are clearly distinct from one another.

“Once again, this illustrates that, although the roles of fission proteins in mitochondrial dynamics and cell death are closely associated, they are clearly distinct from one another.”

Probably not a substantial claim: may not pass S3 (load-bearing).

MOMP is regulated by the relative abundance of pro-apoptotic and anti-apoptotic Bcl-2 family proteins, as well as their subcellular localization and oligomerization states.

“MOMP is regulated by the relative abundance of various pro-apoptotic (e.g. Bax and Bak) and anti-apoptotic proteins of the Bcl-2 family, as well as their subcellular localization and oligomerization states (Kroemer et al., 2007).”

• cites Kroemer et al., 2007 sourceNot checked yet

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Mitochondrial dynamics have been linked to inherited PD and, specifically, to defects in two genes, Parkin (PARK) and PINK1.

“Mitochondrial dynamics have also been linked to inherited PD and, specifically, to defects in two genes, Parkin (PARK) and PINK1 (Dodson and Guo, 2007).”

• cites Dodson and Guo, 2007Not checked yet

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Overexpression of the dominant-negative mutant Drp1K38A induces mitochondrial fusion and confers resistance to apoptosis by preventing a loss of Δψm and inhibiting cytochrome c release.

“The role of mitochondrial dynamics in regulating apoptosis is mainly based on the finding that overexpression of the dominant-negative mutant Drp1K38A induces mitochondrial fusion and confers resistance to apoptosis by preventing a loss of Δψm and inhibiting cytochrome c release (Breckenridge et al., 2003; Brooks et al., 2009; Frank et al., 2001; Karbowski et al., 2002).”

• cites Breckenridge et al., 2003Not checked yet

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• cites Brooks et al., 2009 sourceNot checked yet

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• cites Frank et al., 2001 sourceNot checked yet

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Drp1-mediated release of cytochrome c is selective, as Drp1-induced cristae remodeling does not affect the release of SMAC.

“not affect the release of SMAC (second mitochondrion-derived activator of caspases; also known as Diablo), a pro-apoptotic protein located in the intermembrane space (Arnoult et al., 2005b; Germain et al., 2005; Parone et al., 2006; Scorrano et al., 2002).”

• cites Arnoult et al., 2005bNot checked yet

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• cites Germain et al., 2005Not checked yet

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• cites Parone et al., 2006Not checked yet

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In some cell types, mitochondrial fragmentation occurs following MOMP and cytochrome c release and also in the absence of any detectable cell death.

“However, in some cell types, mitochondrial fragmentation has been shown to occur following MOMP and cytochrome c release (Dinsdale et al., 1999; Gao et al., 2001; Parone et al., 2006; Zhuang et al., 1998) and also in the absence of any detectable cell death (Alirol et al., 2006).”

• cites Dinsdale et al., 1999Not checked yet

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• cites Gao et al., 2001Not checked yet

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• cites Alirol et al., 2006Not checked yet

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Expression of mutant huntingtin (mtHtt) leads to impaired energy metabolism, abnormal Ca2+ signaling and mitochondrial membrane potential, and extensive changes in mitochondrial structure.

“Expression of mutant huntingtin (mtHtt) leads to impaired energy metabolism, abnormal Ca2+ signaling and mitochondrial membrane potential, and extensive changes in mitochondrial structure (Benchoua et al., 2006; Panov et al., 2002; Squitieri et al., 2006).”

• cites Benchoua et al., 2006Not checked yet

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• cites Panov et al., 2002Not checked yet

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• cites Squitieri et al., 2006Not checked yet

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• AssumptionRests on an assumption: Huntington's disease is caused by a mutation in the huntingtin gene (HTT).

May combine two claims.

Downregulation of Fis1 expression significantly enhances fusion and inhibits cell death.

“Similarly to Drp1, downregulation of Fis1 expression significantly enhances fusion and inhibits cell death (Lee et al., 2004).”

• cites Lee et al., 2004Not checked yet

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Mfn2 colocalizes with Drp1 and Bax in mitochondrial foci and directly associates with anti-apoptotic family members and Bak.

“Mfn2 colocalizes with Drp1 and Bax in mitochondrial foci (Karbowski et al., 2002) and directly associates with anti-apoptotic family members (Delivani et al., 2006) and Bak (Brooks et al., 2007).”

• cites Karbowski et al., 2002Not checked yet

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• cites Delivani et al., 2006Not checked yet

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• cites Brooks et al., 2007Not checked yet

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Silencing of Drp1 expression is not associated with reduced translocation of the pro-apoptotic protein Bax to mitochondria, suggesting that Drp1 functions downstream of Bax during apoptosis.

“Moreover, these studies revealed that silencing of Drp1 expression was not associated with reduced translocation of the pro-apoptotic protein Bax to mitochondria, suggesting that Drp1 functions downstream of Bax during apoptosis.”

• cites Breckenridge et al., 2003Not checked yet

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• cites Brooks et al., 2009 sourceNot checked yet

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• cites Frank et al., 2001 sourceNot checked yet

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Apoptosis is elevated during aging of cells and tissues and significantly contributes to cell loss and the pathogenesis of several age-related diseases.

“It is well established that apoptosis is elevated during aging of cells and tissues, and significantly contributes to cell loss and the pathogenesis of several age-related diseases (Marzetti et al., 2008).”

• cites Marzetti et al., 2008 sourceNot checked yet

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Blocking S-nitrosylation of Drp1 attenuates mitochondrial fission and reduces neuronal-cell damage.

“Interestingly, blocking S-nitrosylation of Drp1 attenuates mitochondrial fission and reduces neuronal-cell damage (Cho et al., 2009).”

• cites Cho et al., 2009Not checked yet

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Overexpression of Mfn2, or the inhibition of its presence in mitochondrial foci, prevents the translocation of Bax to mitochondria and/or delays MOMP.

“Moreover, overexpression of Mfn2, or the inhibition of its presence in mitochondrial foci, prevents the translocation of Bax to mitochondria and/or delays MOMP (Karbowski et al., 2006; Neuspiel et al., 2005).”

• cites Karbowski et al., 2006Not checked yet

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• cites Neuspiel et al., 2005Not checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Regulation of mitochondrial dynamics is vital to basic biological processes and for proper mitochondrial function.

“Extensive research has led to the consensus that regulation of mitochondrial dynamics is vital to basic biological processes and for proper mitochondrial function.”

May combine two claims.

The plasticity of mitochondria decreases with age: their capacity for mitochondrial biogenesis is reduced owing to a decline in PGC-1α activity, which might be instigated by an age-related increase in ROS production.

“The plasticity of these organelles decreases with age: their capacity for mitochondrial biogenesis is reduced owing to a decline in PGC-1α activity, which might be instigated by an age-related increase in ROS production (Qiang et al., 2007; Reznick et al., 2007).”

• cites Qiang et al., 2007Not checked yet

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• cites Reznick et al., 2007 sourceNot checked yet

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May combine two claims.

In healthy cells, mitochondrial fusion provides a synchronized internal cable for translocating metabolites and intramitochondrial mixing during biogenesis, whereas mitochondrial division facilitates the equal distribution of mitochondria into daughter cells during mitosis and allows the selective degradation of damaged mitochondria through autophagy.

“In healthy cells, mitochondrial fusion provides a synchronized internal cable for translocating metabolites and intramitochondrial mixing during biogenesis, whereas mitochondrial division facilitates the equal distribution of mitochondria into daughter cells during mitosis and allows the selective degradation of damaged mitochondria through autophagy (Chen and Chan, 2009; Skulachev, 2001).”

• cites Chen and Chan, 2009Not checked yet

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• cites Skulachev, 2001 sourceNot checked yet

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May combine two claims.

Human fibroblasts from PD patients exhibit elevated levels of fragmented mitochondria, which suggests that enhanced fission events are involved in the pathogenesis of human PD.

“By contrast, human fibroblasts from PD patients exhibit elevated levels of fragmented mitochondria, which suggests that enhanced fission events are involved in the pathogenesis of human PD (Exner et al., 2007).”

• cites Exner et al., 2007Not checked yet

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May combine two claims.

These protective mechanisms are markedly impaired in aging and faulty mitochondrial dynamics might be involved in the aging process.

“However, it has become increasingly clear that these protective mechanisms are markedly impaired in aging and that faulty mitochondrial dynamics might be involved in the aging process.”

• AssumptionRests on an assumption: Mitochondria are highly dynamic structures that can adapt their morphology and function in response to a wide range of intracellular and extracellular stimuli.

May combine two claims.

Although studies indicate that mitochondrial fusion and fission pathways are involved in neurodegenerative diseases, the precise roles of these proteins have remained elusive owing to contradictory findings reported in studies of different cell lines and animal models, and with varying pathologies.

“Although these studies indicate that mitochondrial fusion and fission pathways are involved in neurodegenerative diseases, the precise roles of these proteins have remained elusive owing to the contradictory findings that have been reported in studies of different cell lines and animal models, and with varying pathologies.”

May combine two claims.

Autophagy of mitochondria occurs following opening of the mitochondrial permeability transition pore and the depolarization of the mitochondrial membrane, suggesting that autophagy plays a protective role by preventing the cellular damage caused by activation of pro-apoptotic pathways.

“Interestingly, it has also been described that autophagy of mitochondria occurs following opening of the mitochondrial permeability transition pore and the depolarization of the mitochondrial membrane, suggesting that autophagy plays a protective role by preventing the cellular damage caused by activation of pro-apoptotic pathways (Elmore et al., 2001; Kim et al., 2007).”

• cites Elmore et al., 2001Not checked yet

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• cites Kim et al., 2007Not checked yet

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• AssumptionRests on an assumption: Cell-death pathways are induced in postmitotic aging cells, leading to irreversible damage to mitochondrial proteins and DNA, and the loss of nuclei.

Probably not a substantial claim: may not pass S3 (load-bearing).

Muscle mass and function could be preserved during aging and other pathological conditions through physiological stimuli (e.g. exercise) and/or pharmacological intervention.

“In addition, it opens up the possibility that muscle mass and function could be preserved during aging and other pathological conditions through physiological stimuli (e.g. exercise) and/or pharmacological intervention.”

May combine two claims.

In senescent cells, Fis1 expression was found to be reduced in abnormal mitochondria, whereas overexpression of this protein blocked the senescence-related phenotype and maintained cells in a proliferating state.

“This is consistent with investigations of senescent cells: Fis1 expression was found to be reduced in abnormal mitochondria, whereas overexpression of this protein blocked the senescence-related phenotype and maintained cells in a proliferating state (Lee et al., 2007; Yoon et al., 2006).”

• cites Lee et al., 2007Not checked yet

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• cites Yoon et al., 2006Not checked yet

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May combine two claims.

PGC-1α regulates Mfn2 expression, supporting the idea that there is a direct link between mitochondrial biogenesis and mitochondrial morphology.

“The finding that PGC-1α regulates Mfn2 expression supports the idea that there is a direct link between mitochondrial biogenesis and mitochondrial morphology (Cartoni et al., 2005).”

• cites Cartoni et al., 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

In age-related pathologies, energy-challenged mitochondria have disparate levels of fusion and fission proteins and, subsequently, altered mitochondrial morphology.

“This is now apparent in age-related pathologies, wherein energy-challenged mitochondria have disparate levels of fusion and fission proteins and, subsequently, altered mitochondrial morphology.”

May combine two claims.

In yeast, autophagy is required for chronological longevity and for preventing damage to mitochondria in chronologically old cells.

“In yeast, autophagy is required for chronological longevity (Alvers et al., 2009) and for preventing damage to mitochondria in chronologically old cells (A.Y.S., Ashley Alvers, Jennifer Westcott, Michael Wood, Roy Ferraiuolo, Michelle Marraffini et al., unpublished data).”

• cites Alvers et al., 2009Not checked yet

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• cites A.Y.S., Ashley Alvers, Jennifer Westcott, Michael Wood, Roy Ferraiuolo, Michelle Marraffini et al., unpublished dataNot checked yet

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May combine two claims.

The subcellular localization of mitochondria and the overall mitochondrial network in multinucleated muscle fibers are tightly controlled by mitochondrion-shaping proteins, and an imbalance in mitochondrial fusion and fission dynamics probably impairs their function and contributes to the age-related loss of muscle.

“The subcellular localization of mitochondria and the overall mitochondrial network in multinucleated muscle fibers are tightly controlled by mitochondrion-shaping proteins, and an imbalance in mitochondrial fusion and fission dynamics probably impairs their function and contributes to the age-related loss of muscle.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Alterations in mitochondrial function are preceded by or occur concurrently with changes in mitochondrial architecture.

“It is well established that alterations in mitochondrial function are preceded by or occur concurrently with changes in mitochondrial architecture.”

May combine two claims.

In Drosophila, ablation of the genes encoding Parkin and Pink1 seems to promote mitochondrial fusion or inhibit fission, as this phenotype can be rescued by overexpressing the fission protein Drp1 or downregulating the expression of the fusion proteins Mfn2 and Opa1.

“In Drosophila, ablation of the genes encoding Parkin and Pink1 seems to promote mitochondrial fusion or inhibit fission, as this phenotype can be rescued by overexpressing the fission protein Drp1 or downregulating the expression of the fusion proteins Mfn2 and Opa1 (Deng et al., 2008; Poole et al., 2008).”

• cites Deng et al., 2008Not checked yet

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• cites Poole et al., 2008Not checked yet

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