PERK orchestrates MERCS formation and mitochondrial remodelling promoting physiological adaptations during adaptive UPR signalling

Abstract

The transfer of information and metabolites between mitochondria and the ER is mediated by mitochondria-ER contact sites (MERCS), facilitating adaptations following changes in cellular homeostasis. MERCS are dynamic structures, essential for maintaining cellular homeostasis through modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Acute ER stress in myoblasts promoted myogenesis that required the PERK arm of the UPRER for increased MERCS assembly, mitochondrial turnover and function. Similarly, induction of acute UPRER during early development in C. elegans resulted in increased lifespan and healthspan. Adaptive UPRER signalling in myoblasts and C. elegans, increased MERCS assembly and activated autophagy, ultimately promoting mitochondrial remodelling. Adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. The results identify that PERK is required for increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.