Mitochondria are highly dynamic, energy-generating organelles in eukaryotic cells and play an essential role in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and organismal healthspan. Excessive mitochondrial dysfunction and aberrant accumulation of mitochondria in various cell types are shared hallmarks of many pathological conditions and ageing. Thus, maintenance of cellular homeostasis necessitates a tight regulation of mitochondrial biogenesis, as well as, the elimination of dysfunctional or superfluous mitochondria. Mitophagy is a selective type of autophagy mediating removal of damaged mitochondria, and the major degradation pathway, by which cells regulate mitochondrial number in response to metabolic state. However, little is known about the role and regulation of mitophagy during ageing. To address this question, we developed two composite systems for monitoring mitophagy in vivo, and identified conditions that either induce or suppress mitophagy. We used this systems to investigate the involvement of mitophagy in C. elegans ageing. Inhibition of mitophagy does not affect the lifespan of otherwise wild type animals. By contrast, mitophagy depletion markedly shortens the lifespan of long-lived diapause mutants, animals grown under dietary restriction and long-lived mutants with compromised mitochondrial function. We found that mitophagy-deficient animals display impaired mitochondrial function characterized by decreased ATP levels, elevated mitochondrial ROS generation, mitochondrial membrane depolarization, increased oxygen consumption and cytoplasmic Ca2+ elevation. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing the expression of DCT-1 mitophagy receptor. Our results indicate that mitophagy and the retrograde response signalling are tightly coupled and coordinately contribute to promote mitochondrial homeostasis and longevity.
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