Abstract
When mitochondrial respiration or ubiquinone production is inhibited in Caenorhabditis elegans, behavioral rates are slowed and lifespan is extended. Here, we show that these perturbations increase the expression of cell-protective and metabolic genes and the abundance of mitochondrial DNA. This response is similar to the response triggered by inhibiting respiration in yeast and mammalian cells, termed the “retrograde response”. As in yeast, genes switched on in C. elegans mitochondrial mutants extend lifespan, suggesting an underlying evolutionary conservation of mechanism. Inhibition of fstr-1, a potential signaling gene that is up-regulated in clk-1 (ubiquinone-defective) mutants, and its close homolog fstr-2 prevents the expression of many retrograde-response genes and accelerates clk-1 behavioral and aging rates. Thus, clk-1 mutants live in “slow motion” because of a fstr-1/2–dependent pathway that responds to ubiquinone. Loss of fstr-1/2 does not suppress the phenotypes of all long-lived mitochondrial mutants. Thus, although different mitochondrial perturbations activate similar transcriptional and physiological responses, they do so in different ways.
Highlights
Mitochondria generate most of the cell’s energy as well as its reactive oxygen species (ROS), and mitochondrial dysfunction can cause disease and accelerate aging
When respiration is inhibited in C. elegans, rates of behavior and growth are slowed and, interestingly, lifespan is extended
Mutations in clk-1, which inhibit the synthesis of the respiratory-chain factor ubiquinone, produce gene expression, longevity, and behavioral phenotypes similar to those produced by inhibiting components of the respiratory chain
Summary
Mitochondria generate most of the cell’s energy as well as its reactive oxygen species (ROS), and mitochondrial dysfunction can cause disease and accelerate aging. In C. elegans, two types of mutations that affect mitochondrial function increase lifespan. One such mutant, isp-1(qm150), was identified in an EMS screen for mutants with delayed development and defecation rates. Isp-1(qm150), was identified in an EMS screen for mutants with delayed development and defecation rates These animals harbor a mutation in an ironsulfur protein in complex III of the electron transport chain and have reduced rates of oxygen consumption [2]. Two independent RNA interference (RNAi) longevity screens revealed that knock-down of genes encoding components of the respiratory chain or ATP synthase decreased ATP production and rates of respiration, reduced behavioral rates and increased lifespan [3,4]. A mutation that reduces the level of the respiratory-chain component cytochrome c oxidase extends the lifespan of mice [6], suggesting that the underlying mechanism may be conserved in higher animals
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