Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans

Abstract

Mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. An increase of cellular mitochondrial content is characteristic of ageing and numerous pathological conditions in humans, but the underlying cellular and molecular mechanisms have remained unclear. This study shows that the biogenesis and turnover of mitochondria are coupled in Caenorhabditis elegans. Impairment of mitophagy, which removes damaged mitochondria, reduces the worm''s stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor. SKN-1 not only regulates the expression of mitochondrial biogenesis genes but also enhances expression of DCT-1, a key regulator of mitophagy. Uncoupling of these two processes during ageing contributes to the accumulation of damaged mitochondria and decline of cellular function. Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing1,2,3,4,5,6,7,8. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. 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 DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.