Abstract
Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC) can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to-nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age-dependent diseases.
Highlights
Alterations of mitochondrial function broadly impact animal physiology and physiopathology, including aging and age-related diseases
Recent research has shown that a slight dampening of mitochondrial function can dramatically increase the lifespan of a wide range of organisms, suggesting that a similar mechanism likely operates in humans
We discovered that the putative homeobox transcription factor C. elegans homeobox (CEH)-23, which has not previously been implicated in longevity determination, is able to respond to changes in mitochondrial function and in turn causes an extension in lifespan
Summary
Alterations of mitochondrial function broadly impact animal physiology and physiopathology, including aging and age-related diseases. Recent studies revealed that reduced mitochondrial electron transport chain (METC) function can cause substantial longevity increase in a wide range of organisms. Particular METC mutations can greatly extend lifespan. These include mutations in isp-1, which encodes the iron sulfur protein of Complex III [6], and in clk-1, which encodes the hydroxylase protein necessary for the biosynthesis of the METC electron transporter coenzyme Q [7]. Heterozygous loss of the mouse clk-1 homolog (mclk-1) [16] as well as defects in the assembly of the complex IV of the METC [17] extend lifespan. The observation that reduced mitochondrial function can prolong lifespan appears highly conserved among evolutionarily diverse species and is likely to be relevant to human physiology
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