Relationship Between Mitochondrial Electron Transport Chain Dysfunction, Development, and Life Extension in Caenorhabditis elegans

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Abstract
Prior studies have shown that disruption of mitochondrial electron transport chain (ETC) function in the nematode Caenorhabditis elegans can result in life extension. Counter to these findings, many mutations that disrupt ETC function in humans are known to be pathologically life-shortening. In this study, we have undertaken the first formal investigation of the role of partial mitochondrial ETC inhibition and its contribution to the life-extension phenotype of C. elegans. We have developed a novel RNA interference (RNAi) dilution strategy to incrementally reduce the expression level of five genes encoding mitochondrial proteins in C. elegans: atp-3, nuo-2, isp-1, cco-1, and frataxin (frh-1). We observed that each RNAi treatment led to marked alterations in multiple ETC components. Using this dilution technique, we observed a consistent, three-phase lifespan response to increasingly greater inhibition by RNAi: at low levels of inhibition, there was no response, then as inhibition increased, lifespan responded by monotonically lengthening. Finally, at the highest levels of RNAi inhibition, lifespan began to shorten. Indirect measurements of whole-animal oxidative stress showed no correlation with life extension. Instead, larval development, fertility, and adult size all became coordinately affected at the same point at which lifespan began to increase. We show that a specific signal, initiated during the L3/L4 larval stage of development, is sufficient for initiating mitochondrial dysfunction–dependent life extension in C. elegans. This stage of development is characterized by the last somatic cell divisions normally undertaken by C. elegans and also by massive mitochondrial DNA expansion. The coordinate effects of mitochondrial dysfunction on several cell cycle–dependent phenotypes, coupled with recent findings directly linking cell cycle progression with mitochondrial activity in C. elegans, lead us to propose that cell cycle checkpoint control plays a key role in specifying longevity of mitochondrial mutants. The worm Caenorhabditis elegans has afforded major advances in our understanding of aging, in part because a limited number of genetic pathways appear to govern aging in this organism. In this study, we explore one class of long-lived C. elegans, the Mit mutants, which are characterized by defective mitochondrial electron transport chain activity and, hence, ATP production. How disruption of mitochondrial function could lead to life extension has remained a mystery, especially because some of the same genes that cause life extension in worms (including nuo-2 and frh-1), result in pathology in people. Here, we resolve this paradox by showing that life extension of the Mit mutants is limited to a discrete window of electron transport chain dysfunction. We show that the onset of life extension correlates with the disruption of several cell cycle–related phenomena, including larval development, adult size, and fertility and fecundity. We find no overt correlation between levels of oxidative stress and longevity. We propose that life extension in the Mit mutants is intimately connected to DNA checkpoint signaling and that the Mit mutants provide a powerful model for studying human mitochondrial disorders and aging.