Abstract
Mild inhibition of mitochondrial respiration leads to longevity. Disruption of mitochondrial respiratory components extends lifespan in Caenorhabditis elegans, but the effects appear to be complex and the underlying mechanism for lifespan regulation by mitochondrial respiratory genes is still not fully understood. Here, we investigated the role of Y82E9BR.3, a worm homolog of the ATP synthase subunit C, in modulating longevity in C. elegans. We found that the Y82E9BR.3 protein is localized in mitochondria and expressed in various tissues throughout development. RNAi knockdown of Y82E9BR.3 extends lifespan, decreases the accumulation of lipofuscin, and affects various physiological processes, including development delay, reproduction impairment and slow behavior. Further tissue-specific RNAi analysis showed that the intestine is a crucial organ for the longevity effects conferred by Y82E9BR.3 RNAi. Moreover, we demonstrated that lifespan extension by Y82E9BR.3 RNAi is associated with reduced mitochondrial function, as well as the suppression of complex I activity in mitochondria. Unexpectedly, Y82E9BR.3 RNAi knock down did not influence the whole-worm ATP level. Our findings first reveal the crucial role of Y82E9BR.3 in mitochondrial function and the underlying mechanism of how Y82E9BR.3 regulates lifespan in C. elegans.
Highlights
Mitochondria play an essential role in many important physiological processes, including aging
As ATP synthase is highly conserved throughout evolution[14,15], understanding the role of the ATP synthase in lifespan regulation can lead to untangling of the complexity of mitochondrial electron transport chain (ETC) genes in modulating lifespan
It is believed that mitochondria contribute to the lipofuscin accumulation with age, such that the mitochondrial ATP synthase subunit c was found a major component in lipofuscin formed under pathological conditions[23,24]
Summary
Mitochondria play an essential role in many important physiological processes, including aging. The roles of reactive oxygen species (ROS) production and mitochondrial function in aging and lifespan of ETC mutants can be opposite ways[3,4]. One model interpreting these opposite effects is that moderate mitochondrial impairments increase lifespan until a threshold is reached, beyond which animals display wide-spread damage, shortened lifespan, or even death[3,4,13]. Genetic inhibition of the atp-2 gene, which encodes the beta-subunit of F1 domain in complex V, leads to developmental delay and increased lifespan[18]. Our study demonstrated the important role of Y82E9BR.[3] in mitochondrial function and the underlying mechanism involving Y82E9BR.[3] in aging
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