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Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan.

Scialò F, Sriram A, Fernández-Ayala D, Gubina N, Lõhmus M, Nelson G, Logan A, Cooper HM, Navas P, Enríquez JA, Murphy MP, Sanz A - Cell Metab. (2016)

Bottom Line: Here we show that the site of ROS production significantly contributes to their apparent dual nature.Furthermore, preventing ubiquinone reduction, through knockdown of PINK1, shortens lifespan and accelerates aging; phenotypes that are rescued by increasing reverse electron transport.These results illustrate that the source of a ROS signal is vital in determining its effects on cellular physiology and establish that manipulation of ubiquinone redox state is a valid strategy to delay aging.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

No MeSH data available.


Related in: MedlinePlus

NDI1-Mediated ROS Production Rescues Superoxide-Mediated Mitochondrial Dysfunction(A) Representative images of fly brains from indicated genotypes stained with MitoSOX.(B) Quantification of (A) (n = 5).(C) Survival curves of the indicated genotypes (n = 180–380).(D) Mitochondrial respiration in flies of the indicated genotypes (n = 6).(E) CI, CII, and aconitase enzymatic activities in flies of the indicated genotypes (n = 7).Values shown represent means ± SEM of at least three biological replicates, unless otherwise stated. See also Figure S3 and Table S1 for statistical analysis of survival curves.
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fig3: NDI1-Mediated ROS Production Rescues Superoxide-Mediated Mitochondrial Dysfunction(A) Representative images of fly brains from indicated genotypes stained with MitoSOX.(B) Quantification of (A) (n = 5).(C) Survival curves of the indicated genotypes (n = 180–380).(D) Mitochondrial respiration in flies of the indicated genotypes (n = 6).(E) CI, CII, and aconitase enzymatic activities in flies of the indicated genotypes (n = 7).Values shown represent means ± SEM of at least three biological replicates, unless otherwise stated. See also Figure S3 and Table S1 for statistical analysis of survival curves.

Mentions: If ROS signaling is site specific and works to maintain mitochondrial function, we hypothesized that it should be possible for beneficial ROS signaling to rescue deleterious mitochondrial phenotypes induced by oxidative stress. To test this, we knocked down SOD2 (the only mitochondrial matrix superoxide dismutase in Drosophila; Figure S3A) and observed a significant increase in levels of superoxide in fly brains (Figures 3A and 3B) while levels of mtH2O2 were significantly decreased (Figure S3B, right), which is in agreement with the reported positive correlation between SOD2 activity and mtH2O2 levels (Rodríguez et al., 2000). SOD2 knockdown dramatically shortened longevity (Figure 3C) and, in addition, severely affected CI-respiration (Figure 3D), with a significant decrease in the enzymatic activity of CI, CII, and aconitase (Figure 3E). Western blot analysis showed that levels of CI and aconitase were unchanged (Figure S3D), suggesting that, as has been shown for aconitase, high levels of superoxide inhibit the activity of these enzymes (Gardner and Fridovich, 1992). Mitochondrial ultrastructure from dissected dorsal flight muscle was unaffected by SOD2 knockdown (Figures S3E and S3F), showing that high levels of superoxide recapitulate some (e.g., increased mortality and, decreased CI activity), but not all features of aging (e.g., alteration in mitochondrial morphology). Although high levels of superoxide in the absence of SOD2 are detrimental, this situation is unlikely to occur in vivo in aged flies since SOD2 levels (Figures S1G and S1H) and superoxide dismutase activity (Sohal et al., 1990) are reported to increase with age.


Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan.

Scialò F, Sriram A, Fernández-Ayala D, Gubina N, Lõhmus M, Nelson G, Logan A, Cooper HM, Navas P, Enríquez JA, Murphy MP, Sanz A - Cell Metab. (2016)

NDI1-Mediated ROS Production Rescues Superoxide-Mediated Mitochondrial Dysfunction(A) Representative images of fly brains from indicated genotypes stained with MitoSOX.(B) Quantification of (A) (n = 5).(C) Survival curves of the indicated genotypes (n = 180–380).(D) Mitochondrial respiration in flies of the indicated genotypes (n = 6).(E) CI, CII, and aconitase enzymatic activities in flies of the indicated genotypes (n = 7).Values shown represent means ± SEM of at least three biological replicates, unless otherwise stated. See also Figure S3 and Table S1 for statistical analysis of survival curves.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4835580&req=5

fig3: NDI1-Mediated ROS Production Rescues Superoxide-Mediated Mitochondrial Dysfunction(A) Representative images of fly brains from indicated genotypes stained with MitoSOX.(B) Quantification of (A) (n = 5).(C) Survival curves of the indicated genotypes (n = 180–380).(D) Mitochondrial respiration in flies of the indicated genotypes (n = 6).(E) CI, CII, and aconitase enzymatic activities in flies of the indicated genotypes (n = 7).Values shown represent means ± SEM of at least three biological replicates, unless otherwise stated. See also Figure S3 and Table S1 for statistical analysis of survival curves.
Mentions: If ROS signaling is site specific and works to maintain mitochondrial function, we hypothesized that it should be possible for beneficial ROS signaling to rescue deleterious mitochondrial phenotypes induced by oxidative stress. To test this, we knocked down SOD2 (the only mitochondrial matrix superoxide dismutase in Drosophila; Figure S3A) and observed a significant increase in levels of superoxide in fly brains (Figures 3A and 3B) while levels of mtH2O2 were significantly decreased (Figure S3B, right), which is in agreement with the reported positive correlation between SOD2 activity and mtH2O2 levels (Rodríguez et al., 2000). SOD2 knockdown dramatically shortened longevity (Figure 3C) and, in addition, severely affected CI-respiration (Figure 3D), with a significant decrease in the enzymatic activity of CI, CII, and aconitase (Figure 3E). Western blot analysis showed that levels of CI and aconitase were unchanged (Figure S3D), suggesting that, as has been shown for aconitase, high levels of superoxide inhibit the activity of these enzymes (Gardner and Fridovich, 1992). Mitochondrial ultrastructure from dissected dorsal flight muscle was unaffected by SOD2 knockdown (Figures S3E and S3F), showing that high levels of superoxide recapitulate some (e.g., increased mortality and, decreased CI activity), but not all features of aging (e.g., alteration in mitochondrial morphology). Although high levels of superoxide in the absence of SOD2 are detrimental, this situation is unlikely to occur in vivo in aged flies since SOD2 levels (Figures S1G and S1H) and superoxide dismutase activity (Sohal et al., 1990) are reported to increase with age.

Bottom Line: Here we show that the site of ROS production significantly contributes to their apparent dual nature.Furthermore, preventing ubiquinone reduction, through knockdown of PINK1, shortens lifespan and accelerates aging; phenotypes that are rescued by increasing reverse electron transport.These results illustrate that the source of a ROS signal is vital in determining its effects on cellular physiology and establish that manipulation of ubiquinone redox state is a valid strategy to delay aging.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

No MeSH data available.


Related in: MedlinePlus