InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics

This narrow line between benefit and pathology necessitates better understanding of the adaptations that distinguish between these opposing outcomes. The conserved ER calcium channel, InsP3R, represents an underexplored control point for mitochondrial adaptations, as it promotes mitochondrial homeostasis through direct matrix calcium flux and diverse cytosolic pathways.

Here we reveal that longevity induced by Complex I inhibition is dependent on InsP3R function, and use C. elegans to dissect the importance of the potentially diverse routes by which intracellular calcium can regulate mitochondrial functions. Although we find the InsP3R potently stimulates mitochondrial bioenergetics; surprisingly, the mitochondrial calcium uniporter is dispensable for respiration and lifespan, indicating InsP3R signaling promotes adaptation independently of ER-to-matrix calcium flux.