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

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.

Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging

“…The underlying mechanisms have mainly been proposed to be via suppression of microglial activation, neuroinflammation, and oxidative stress [9] [47]. During conditions of oxidative stress, e.g., induced by mitochondrial dysfunction, SKN-1 is imported to nuclei, where it activates a coordinated transcription response [48,49]. Interestingly, the gradual upregulation of skn-1 expression with age was to a large extent abrogated in krill oil treated animals.…”

“…Functional enrichment of immunity and stress response pathways reflected a general anti-inflammatory effect of krill oil, exemplified with regulation of SKN-1, a master regulator of oxidative stress responses in C. elegans [ 47 ]. During conditions of oxidative stress, e.g., induced by mitochondrial dysfunction, SKN-1 is imported to nuclei, where it activates a coordinated transcription response [ 48 , 49 ]. Interestingly, the gradual upregulation of skn-1 expression with age was to a large extent abrogated in krill oil treated animals.…”

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond

“…[115] In nematodes, de novo serine biosynthesis is required for MitoMISS associated longevity, while, folate and methionine intermediates display reduced levels across different canonical longevity mutants. [110,139] In flies, dATF4 activates the mitochondrial branch of one carbon metabolism conferring neuroprotection in pink1 and parkin mutants. [140] These findings suggest that UPR mt /ISR-driven metabolic reprogramming may confer different outcomes upon distinct mitochondrial insults.…”

Investigating the Impact of a Curse: Diseases, Population Isolation, Evolution and the Mother’s Curse

“…However, aging is also a process that exerts large differences between the two sexes, since females tend to live longer than males, although they are considered to have a poorer health associated with a greater comorbidity [ 77 , 78 , 79 , 80 ]. Taking into account the key role of mitochondria and the mitochondrial genome in aging [ 81 , 82 , 83 ], as there is an increase in the amount of evidence linking the mtDNA variants with age-related diseases [ 84 ], and highlighting the role of mtDNA in the regulation of the lifespan [ 85 , 86 ], several studies indicate that the MC effect can contribute to the longevity gap observed between the sexes.…”