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

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Chen and Chan, 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Smirnova et al., 2001

In the paper

“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).”

What the sources say

• Not checked yetcites Bach et al., 2003 source
• Not checked yetcites Chen et al., 2005 source
• Not checked yetcites Pich et al., 2005

In the paper

“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).”

What the sources say

• Not checked yetcites Fannin et al., 1999
• Not checked yetcites Sugiyama et al., 1993

In the paper

“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).”

What the sources say

• Not checked yetcites Bach et al., 2003 source
• Not checked yetcites Santel et al., 2003

In the paper

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

What the sources say

• Not checked yetcites Yoon et al., 2003

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Arnoult et al., 2005a
• Not checked yetcites Duvezin-Caubet et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Chomyn and Attardi, 2003
• Not checked yetcites Harman, 1972

In the paper

“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).”

What the sources say

• Not checked yetcites Harman, 1956 source

In the paper

“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).”

What the sources say

• Not checked yetcites Ishihara et al., 2004 source

In the paper

“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).”

What the sources say

• Not checked yetcites Wasilewski and Scorrano, 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Pitts et al., 1999
• Not checked yetcites Arnoult et al., 2005b

In the paper

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

What the sources say

• Not checked yetcites Frezza et al., 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Sesaki and Jensen, 1999

In the paper

“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).”

What the sources say

• Not checked yetcites Kujoth et al., 2005 source
• Not checked yetcites Trifunovic et al., 2004 source

In the paper

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

What the sources say

• Not checked yetcites Wasilewski and Scorrano, 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Hutter et al., 2007 source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Chen et al., 2003 source
• Not checked yetcites Eura et al., 2003

In the paper

“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).”

What the sources say

• Not checked yetcites Chen et al., 2007
• Not checked yetcites Sato et al., 2006
• Not checked yetcites Sato et al., 2009

In the paper

“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.”

What the sources say

• Not checked yetcites Twig et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hermann et al., 1998
• Not checked yetcites Rapaport et al., 1998

In the paper

“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).”

What the sources say

• Not checked yetcites Gomes and Scorrano, 2008
• Not checked yetcites Twig et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites Liu et al., 1996 source
• Not checked yetcites Susin et al., 1999
• Not checked yetcites Kroemer et al., 2007 source

In the paper

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

What the sources say

• Not checked yetcites Green and Kroemer, 2004

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2007
• Not checked yetcites Yoon et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2007
• Not checked yetcites Yoon et al., 2006

In the paper

“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.”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites James et al., 1996

In the paper

“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).”

What the sources say

• Not checked yetcites Qiang et al., 2007
• Not checked yetcites Reznick et al., 2007 source

In the paper

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

What the sources say

• Not checked yetcites Green, 1998

In the paper

“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).”

What the sources say

• Not checked yetcites Wallace and Fan, 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Donati et al., 2001
• Not checked yetcites Terman, 1995
• Not checked yetcites Wohlgemuth et al., 2010 source

In the paper

“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.”

What the sources say

• Not checked yetcites Narendra et al., 2008 source

In the paper

“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.”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Parone et al., 2008 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dirks and Leeuwenburgh, 2005
• Not checked yetcites Dupont-Versteegden, 2005
• Not checked yetcites Seo et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Wasiak et al., 2007
• Not checked yetcites Chang and Blackstone, 2007
• Not checked yetcites Cribbs and Strack, 2007

In the paper

“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).”

What the sources say

• Not checked yetcites Olichon et al., 2003 source

In the paper

“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).”

What the sources say

• Not checked yetcites Cho et al., 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Bossy-Wetzel et al., 2008

In the paper

“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.”

What the sources say

• Not checked yetcites Wang et al., 2008
• Not checked yetcites Cho et al., 2009

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Kroemer et al., 2007 source

In the paper

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

What the sources say

• Not checked yetcites Dodson and Guo, 2007

In the paper

“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).”

What the sources say

• Not checked yetcites Breckenridge et al., 2003
• Not checked yetcites Brooks et al., 2009 source
• Not checked yetcites Frank et al., 2001 source

In the paper

“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).”

What the sources say

• Not checked yetcites Arnoult et al., 2005b
• Not checked yetcites Germain et al., 2005
• Not checked yetcites Parone et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Dinsdale et al., 1999
• Not checked yetcites Gao et al., 2001
• Not checked yetcites Alirol et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Benchoua et al., 2006
• Not checked yetcites Panov et al., 2002
• Not checked yetcites Squitieri et al., 2006

In the paper

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

What the sources say

• Not checked yetcites Lee et al., 2004

In the paper

“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).”

What the sources say

• Not checked yetcites Karbowski et al., 2002
• Not checked yetcites Delivani et al., 2006
• Not checked yetcites Brooks et al., 2007

In the paper

“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.”

What the sources say

• Not checked yetcites Breckenridge et al., 2003
• Not checked yetcites Brooks et al., 2009 source
• Not checked yetcites Frank et al., 2001 source

In the paper

“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).”

What the sources say

• Not checked yetcites Marzetti et al., 2008 source

In the paper

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

What the sources say

• Not checked yetcites Cho et al., 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Karbowski et al., 2006
• Not checked yetcites Neuspiel et al., 2005

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Qiang et al., 2007
• Not checked yetcites Reznick et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites Chen and Chan, 2009
• Not checked yetcites Skulachev, 2001 source

In the paper

“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).”

What the sources say

• Not checked yetcites Exner et al., 2007

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Elmore et al., 2001
• Not checked yetcites Kim et al., 2007

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2007
• Not checked yetcites Yoon et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Cartoni et al., 2005

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Alvers et al., 2009
• Not checked yetcites A.Y.S., Ashley Alvers, Jennifer Westcott, Michael Wood, Roy Ferraiuolo, Michelle Marraffini et al., unpublished data

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Deng et al., 2008
• Not checked yetcites Poole et al., 2008