Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans.
Starvation significantly alters cellular physiology, and signs of aging have been reported to occur during starvation. Mitochondria are essential to the regulation of cellular energetics and aging. We sought to determine whether mitochondria exhibit signs of aging during starvation and whether quality control mechanisms regulate mitochondrial physiology during starvation. We describe effects of starvation on mitochondria in the first and third larval stages of the nematode Caenorhabditis elegans. When starved, C. elegans larvae enter developmental arrest. We observed fragmentation of the mitochondrial network, a reduction in mitochondrial DNA (mtDNA) copy number, and accumulation of DNA damage during starvation-induced developmental arrest. Mitochondrial function was also compromised by starvation. Starved worms had lower basal, maximal, and ATP-linked respiration. These observations are consistent with reduced mitochondrial quality, similar to mitochondrial phenotypes during aging. Using pharmacological and genetic approaches, we found that worms deficient for autophagy were short-lived during starvation and recovered poorly from extended starvation, indicating sensitivity to nutrient stress. Autophagy mutants unc-51/Atg1 and atg-18/Atg18 maintained greater mtDNA content than wild-type worms during starvation, suggesting that autophagy promotes mitochondrial degradation during starvation. unc-51 mutants also had a proportionally smaller reduction in oxygen consumption rate during starvation, suggesting that autophagy also contributes to reduced mitochondrial function. Surprisingly, mutations in genes involved in mitochondrial fission and fusion as well as selective mitophagy of damaged mitochondria did not affect mitochondrial content during starvation. Our results demonstrate the profound influence of starvation on mitochondrial physiology with organismal consequences, and they show that these physiological effects are influenced by autophagy.
Hibshman, JD; Leuthner, TC; Shoben, C; Mello, DF; Sherwood, DR; Meyer, JN; Baugh, LR
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