Longevity-promoting mitochondrial unfolded protein response activation requires elements of the PeBoW complex

Abstract

Mitochondria play a crucial role in cellular energy metabolism and homeostasis, with their dysfunction implicated in aging and various diseases. The mitochondrial unfolded protein response (UPRmt) is a conserved stress response that maintains mitochondrial proteostasis and is linked to lifespan regulation in multiple species. In C. elegans, UPRmt activation occurs upon mitochondrial stress, involving key transcription factors such as ATFS-1 and other regulatory components. The voltage-dependent anion channel (VDAC), located on the outer mitochondrial membrane, facilitates metabolite transport. Dysregulation of VDAC levels has been associated with cancer, neurodegeneration, and metabolic disorders. Previously, we demonstrated that elevated VDAC-1 levels in C. elegans lead to increased mitochondrial permeability and reduced lifespan. In this study, we investigate the effects of VDAC-1 knockdown on longevity. Unexpectedly, we find that VDAC-1 depletion extends lifespan through the activation of UPRmt, similar to the effects observed with impaired electron transport chain components. Furthermore, we identify the PeBoW complex as a critical mediator of UPRmt activation following VDAC-1 loss. Our findings reveal a novel regulatory role for PeBoW in UPRmt induction and lifespan extension in response to mitochondrial stress, highlighting its essential function in mitochondrial quality control and longevity pathways.