Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice

Miwa, Soichi; Jow, Howsun; Baty, Karen; Johnson, Amy J.; Czapiewski, Rafal; Saretzki, Gabriele; Treumann, Achim; Zglinicki, Thomas von

doi:10.1038/ncomms4837

Cited by 180 publications

(172 citation statements)

References 70 publications

(91 reference statements)

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“…However, neither abundance nor turnover of ND‐1 changed with age in either muscle. The nonuniform effects of age on complex I subunit abundance reported here are consistent with the loss of coordination between nuclear and mitochondrial‐encoded subunits of the respiratory chain recently described in aging muscle (Gomes et al ., 2013; Miwa et al ., 2014), although the change reported here (increased nuclear‐encoded and ND5 subunits) was dissimilar to that reported by Gomes et al . (decreased mitochondrial‐encoded subunits).…”

Section: Discussioncontrasting

confidence: 92%

“…(decreased mitochondrial‐encoded subunits). Increased content of complex I proteins with age, specifically those of the matrix arm, has been linked to decreased lifespan and oxidative stress (Miwa et al ., 2014); thus, a breakdown in stoichiometry in respiratory subunits is expected to lead to poor assembly and function of complex I that would result in the decreased mitochondrial respiratory efficiency and elevated mitochondrial oxidative stress observed here. Our data further implicate complex I as a focal point for regulation of mitochondrial quality and age‐related changes in mitochondrial function.…”

Section: Discussionmentioning

confidence: 88%

“…Inhibition of over half the maximal activity of complex I does not necessarily result in a commensurate decrease of in vivo basal ATP synthase activity (Kruse et al ., 2008). However, changes in complex I stoichiometry can affect the efficiency of electron transfer and result in oxidative stress (Miwa et al ., 2014) and slight alterations of the redox status of electron donors such as NAD/NADH can have genomewide effects (Imai & Guarente, 2014). Mitochondrial dysfunction is repeatedly at the forefront of age‐related disease.…”

Section: Introductionmentioning

confidence: 99%

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Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

et al. 2015

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SummaryChanges in mitochondrial function with age vary between different muscle types, and mechanisms underlying this variation remain poorly defined. We examined whether the rate of mitochondrial protein turnover contributes to this variation. Using heavy label proteomics, we measured mitochondrial protein turnover and abundance in slow‐twitch soleus (SOL) and fast‐twitch extensor digitorum longus (EDL) from young and aged mice. We found that mitochondrial proteins were longer lived in EDL than SOL at both ages. Proteomic analyses revealed that age‐induced changes in protein abundance differed between EDL and SOL with the largest change being increased mitochondrial respiratory protein content in EDL. To determine how altered mitochondrial proteomics affect function, we measured respiratory capacity in permeabilized SOL and EDL. The increased mitochondrial protein content in aged EDL resulted in reduced complex I respiratory efficiency in addition to increased complex I‐derived H2O2 production. In contrast, SOL maintained mitochondrial quality, but demonstrated reduced respiratory capacity with age. Thus, the decline in mitochondrial quality with age in EDL was associated with slower protein turnover throughout life that may contribute to the greater decline in mitochondrial dysfunction in this muscle. Furthermore, mitochondrial‐targeted catalase protected respiratory function with age suggesting a causal role of oxidative stress. Our data clearly indicate divergent effects of age between different skeletal muscles on mitochondrial protein homeostasis and function with the greatest differences related to complex I. These results show the importance of tissue‐specific changes in the interaction between dysregulation of respiratory protein expression, oxidative stress, and mitochondrial function with age.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

et al. 2015

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“…3C). This is consistent with recent work showing different states of subcomplex I aggregates in aging (32). Interestingly, we observed that the only complex I subunit that was distributed equally in both cell types was NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) (Fig.…”

Section: Modulation Of Complex I Assembly Into Supercomplexes Alters Rossupporting

confidence: 81%

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

López-Fabuel

Douce

Logan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

324

278

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Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.redox | brain | bioenergetics | lactate | glycolysis T he brain is a metabolically demanding organ (1) that requires tight cooperation between neurons and astrocytes (2). Astrocytes provide crucial metabolic and structural support (3, 4) and are key players in neurotransmission (5-7) and behavior (8). The status of many major redox couples in the brain is also regulated by astrocytes (9), through their high content of antioxidant compounds and enzymes (10) and by the constitutive stabilization of the master antioxidant transcriptional activator, nuclear factor erythroid 2-related factor 2 (Nrf2) (11). Thus, astrocytes are equipped to protect themselves when exposed to excess reactive oxygen species (ROS) (12) and reactive nitrogen species (13,14). Moreover, astrocytes also provide nearby neurons with protective antioxidant precursors through a cell-signaling mechanism involving glutamate receptor activation by neurotransmission (11,15,16). The tight coupling between astrocytes and neurons therefore helps in energy and redox metabolism during normal brain function.Intriguingly, the ATP used by neurons is supplied by oxidative phosphorylation, whereas most energy needs of astrocytes are met by glycolysis (17). In fact, the survival of neurons requires oxidative phosphorylation (18,19). The different energy metabolisms of the two cell types are closely coupled, with astrocytes releasing the glycolytic end product, lactate, which is used by neighboring neurons to drive oxidative phosphorylation (20)(21)(22). As the molecular mechanisms underlying the markedly different modes of ATP production in the two cell types are not understood, we investigated whether the organization of the mitochondrial respiratory chain in brain cells could contribute. Here, we report that the extent of supercomplex f...

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“…24 who showed significant down‐regulation of prohibitin under oxidative stress in the rat testis induced by doxorubicin injection. The present report is the first to show the involvement of PHB in mitochondrial ROS generation of human sperm, consistent with the findings in endothelial 12 and Hela cells 25. The mechanism for the increased generation of mitochondrial ROS might be related to a disruption of mitochondrial electron transport flow in complex I of mitochondrial inner membrane, as reported by Koppers et al .…”

Section: Discussionsupporting

confidence: 93%

Prohibitin involvement in the generation of mitochondrial superoxide at complex I in human sperm

Chai

Chen

Shi

et al. 2016

J Cellular Molecular Medi

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Prohibitin (PHB), a major mitochondrial membrane protein, has been shown earlier in our laboratoryto regulate sperm motility via an alteration in mitochondrial membrane potential (MMP) in infertile men with poor sperm quality. To test if PHB expression is associated with sperm mitochondrial superoxide (mROS) levels, here we examined sperm mROS levels, high MMP and lipid peroxidation in infertile men with poor sperm motility (asthenospermia, A) and/or low sperm concentrations (oligoasthenospermia, OA). The diaphorase‐type activity of sperm mitochondrial complex I (MCI) and PHB expression were also determined. We demonstrate that mROS and lipid peroxidation levels are significantly higher in sperm from A and OA subjects than in normospermic subjects, whereas high MMP and PHB expression are significantly lower. A positive correlation between mROS and lipid peroxidation and a negative correlation of mROS with PHB expression, high MMP, and sperm motility were found in these subjects. The finding of similar diaphorase‐type activity levels of sperm MCI in the three groups studied suggests that the catalytic subunits of MCI in the matrix arm may produce mROS on its own. There may be a dysfunction of electron transport at MCI associated with decreased expression of PHB in sperm with poor quality. We conclude that mROS level is increased and associated with decreased PHB expression, and it may regulate sperm motility via increases in low MMP and lipid peroxidation. This is the first report on the involvement of PHB in human sperm motility loss associated with increased generation of mROS at MCI.

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Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice

Cited by 180 publications

References 70 publications

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

Prohibitin involvement in the generation of mitochondrial superoxide at complex I in human sperm

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