Nonselective autophagy reduces mitochondrial content during starvation in Caenorhabditis elegans

Abstract

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 if 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 autophagy promotes mitochondrial degradation during starvation. unc-51 mutants also had a proportionally smaller reduction in oxygen consumption rate during starvation, suggesting 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.

Nutrient status shapes selfish mitochondrial genome dynamics across different levels of selection

“…Disrupting either of these processes did not restore mtDNA copy number in daf-2 mutants ( Figure 4A,B ), nor did we observe increased germline apoptosis in daf-2 mutants ( Figure 4—figure supplement 1A,B ). Because mitochondrial degradation can occur in a PINK1/Parkin-independent manner ( Allen et al, 2013 ; Di Rita et al, 2018 ; Hibshman et al, 2018 ), we therefore also tested for a potential role of mitochondrial fission, a common precursor of mitophagy, using a deletion in the gene drp-1 , which encodes a dynamin-related protein important for mitochondrial fission. Although we observed an increase in mtDNA copy number when mitochondrial fission is disrupted in animals with intact insulin signaling ( Figure 4C ), consistent with reduced mitophagy, we did not observe a rescue of mtDNA copy number in daf-2 These data suggest that the suppression of mtDNA content upon loss of insulin signaling is not mediated through the elimination of mitochondria by PINK/Parkin-dependent mitophagy, mitochondrial fission, or apoptosis.…”

Neuronal SKN-1B modulates nutritional signalling pathways and mitochondrial networks to control satiety

“…Mitochondria are dynamic organelles that change their network morphology, balancing their fission with fusion to maximise energy production [ 8 , 39 , 41 ]. In worms their morphology has been shown to change in response to starvation [ 42 ] as well as various DR protocols [ 39 , 43 ], and can be used to provide clues about an animal’s physiological state. In addition skn-1 has previously been implicated in the maintenance of muscle mitochondrial networks, and anoxia-induced mitochondrial dynamics, raising the question of whether these phenomena might be mediated by skn-1b [ 44 , 45 ].…”

C. elegans electrotaxis behavior is modulated by heat shock response and unfolded protein response signaling pathways

“…At the cellular level, starvation induces both mitochondrial and ER stress 53,80,84 . Mitochondria become fragmented in starved animals and are cleared through mitophagy 10,80,85 . Zhang et al 86 reported that starvation caused ER stress and led to activation of PERK/eIF2α in an astrocyte cell line.…”