Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis

Mitochondrial function is linked to lifespan. Here the authors show that inhibition of mitochondrial protein import leads to a reduction in mitochondrial abundance and extends lifespan in Caenorhabditis elegans via activation of glycolysis and de novo serine biosynthesis. Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

Automated summary

Inhibition of mitochondrial protein import reduces mitochondrial abundance and extends lifespan in Caenorhabditis elegans. This effect is mediated by activation of glycolysis and de novo serine biosynthesis. The study also shows that mitochondrial chaperone induction is not essential for lifespan extension.