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.
Highlights
In humans, many mutations that compromise mitochondrial functionality lead to a variety of pathological, lifeshortening diseases [1]
We explore one class of long-lived C. elegans, the Mit mutants, which are characterized by defective mitochondrial electron transport chain activity and, adenosine triphosphate (ATP) production
Dillin and colleagues [6], reported that the lifespan of wildtype C. elegans (N2) can be increased by approximately 30% when treated with a bacterial RNA interference (RNAi) feeding construct against atp-3
Summary
Many mutations that compromise mitochondrial functionality lead to a variety of pathological, lifeshortening diseases [1]. FXN encodes frataxin, a 155–amino acid protein that plays an essential role in mitochondrial iron storage, Fe2þ detoxification, and Fe-S cluster assembly and, in the functionality of other mitochondrial proteins such as aconitase and complexes I, II, and III of the electron transport chain (ETC) [3,4]. It is surprising, to learn that in C. elegans, a large class of mutants with disruptions (either genetic or RNA interference (RNAi)-mediated) in genes essential for the function of mitochondrial ETC—the socalled Mit (mitochondrial) mutants [5]—are long-lived. How can loss of genes that are expected to be critical for both cellular energy production and proper mitochondrial functionality result in life extension in the C. elegans Mit mutants? Until now, most ideas have revolved around reduced mitochondrial
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