Abstract
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.
Highlights
Sustained mitochondrial fitness relies on coordinated biogenesis and clearance
We show that inhibition of the main routes for mitochondrial protein import, leading to mitochondrial mass reduction, activates the organellar proteostatic mechanism, mitochondrial unfolded protein response (UPRmt), which in sequence, triggers a longevity paradigm that diverges from the established nutrient-sensing and mild mitochondrial dysfunction pathways
Import of the vast majority of mitochondrial proteins is mediated by four main translocase complexes, the outer membrane (TOM), translocase of inner membrane 23 (TIM23), translocase of inner membrane 22 (TIM22), and SAM/TOB (Supplementary Fig. 1a)
Summary
Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Dysfunctional mitochondria have been shown to accrue with age in several organisms and correlate with a plethora of late-onset life-threatening diseases, like neurodegenerative disorders, cardiovascular diseases, and cancer[2,3,4,5] This relationship could be attributed to a higher pace of mutation accumulation on mitochondrial DNA (mtDNA), clonal expansion of mutated mtDNA, and age-dependent decline of organelle-specific quality control mechanisms[6,7,8,9]. Increased mitochondrial biogenesis ensures the building of a robust and healthy mitochondrial network, accumulation of dysfunctional organelles, which often accompanies aging and age-associated diseases, can be detrimental for organismal physiology. We show that inhibition of the main routes for mitochondrial protein import, leading to mitochondrial mass reduction, activates the organellar proteostatic mechanism, mitochondrial unfolded protein response (UPRmt), which in sequence, triggers a longevity paradigm that diverges from the established nutrient-sensing and mild mitochondrial dysfunction pathways. Combined metabolomic and genetic analysis provided significant leads on the mechanisms underlying this phenomenon, extending our understanding on the biological processes influencing aging and longevity
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