A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes

Ishii, Naoaki; Fujii, Michihiko; Hartman, Paul A.; Tsuda, Michio; Yasuda, Kayo; Senoo‐Matsuda, Nanami; Yanase, Sumino; Ayusawa, Dai; Suzuki, Kenshi

doi:10.1038/29331

Cited by 642 publications

(434 citation statements)

References 25 publications

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“…Recently, yet another level of protection from damage was discovered: an alteration in succinate dehydrogenase cytochrome b which results in decreased electron transport through complex II leads to extreme hypersensitivity to oxygen in C. elegans (121). This supports an earlier finding by Guidot et al (122) showing that mitochondria play a role not only in the production of ROS, but in their ultimate disposal.…”

Section: Mechanisms For Mitochondrial Dna Maintenancesupporting

confidence: 64%

Mitochondria, oxidative DNA damage, and aging

Anson

Bohr

2000

AGE

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Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, MnSOD -/+ mice incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences.

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Section: Mechanisms For Mitochondrial Dna Maintenancesupporting

confidence: 64%

Mitochondria, oxidative DNA damage, and aging

Anson

Bohr

2000

AGE

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“…Methyl viologen‐sensitive gene ( mev‐1 ) is a subunit of succinate coenzyme Q oxidoreductase that is a part of complex II of the electron transport system in the mitochondria. C. elegans mev‐1 mutants show increased levels of intrinsic oxidative stress because of increased superoxide anion formation (Ishii et al ., 1998), and we observed that feeding with LG2055 extended the lifespan of the C. elegans mev‐1 mutant (Fig. 2c and Table S1).…”

Section: Resultsmentioning

confidence: 70%

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

et al. 2015

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SummaryLactic‐acid bacteria are widely recognized beneficial host associated groups of the microbiota of humans and animals. Some lactic‐acid bacteria have the ability to extend the lifespan of the model animals. The mechanisms behind the probiotic effects of bacteria are not entirely understood. Recently, we reported the benefit effects of Lactobacillus gasseri SBT2055 (LG2055) on animal and human health, such as preventing influenza A virus, and augmentation of IgA production. Therefore, it was preconceived that LG2055 has the beneficial effects on longevity and/or aging. We examined the effects of LG2055 on lifespan and aging of Caenorhabditis elegans and analyzed the mechanism of prolongevity. Our results demonstrated that LG2055 has the beneficial effects on longevity and anti‐aging of C. elegans. Feeding with LG2055 upregulated the expression of the skn‐1 gene and the target genes of SKN‐1, encoding the antioxidant proteins enhancing antioxidant defense responses. We found that feeding with LG2055 directly activated SKN‐1 activity via p38 MAPK pathway signaling. The oxidative stress response is elicited by mitochondrial dysfunction in aging, and we examined the influence of LG2055 feeding on the membrane potential of mitochondria. Here, the amounts of mitochondria were significantly increased by LG2055 feeding in comparison with the control. Our result suggests that feeding with LG2055 is effective to the extend lifespan in C. elegans by a strengthening of the resistance to oxidative stress and by stimulating the innate immune response signaling including p38MAPK signaling pathway and others.

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“…fumarate but cannot transfer electrons to UbQ, resulting in increased ROS levels and premature ageing (Ishii et al, 1998). This can be reconciled with a recent study suggesting that the Q P site is important for electron channelling between UbQ and the juxtapositioned haem group , which contributes to stabilization of the transient ubisemiquinone radical (Tran et al, 2006).…”

Section: Complex II As An Anti-cancer Drug Target L-f Dong Et Almentioning

confidence: 94%

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

et al. 2008

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a-Tocopheryl succinate (a-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of a-TOS has not been identified. Here, we show that a-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of a-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of a-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to a-TOS. We propose that a-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

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A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes

Cited by 642 publications

References 25 publications

Mitochondria, oxidative DNA damage, and aging

Mitochondria, oxidative DNA damage, and aging

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

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