InsP3R Signaling and Actomyosin-Dependent Mitochondrial Dynamics in Mitochondrial Stress-Induced Longevity
Mitochondrial perturbations confer longevity or disease depending on whether cells successfully adapt. Here, the authors show that ER calcium signalling promotes longevity during mitochondrial stress by regulating actin-
Mitochondrial impairment can confer longevity, while disease-associated mitochondrial dysfunction triggers pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here, we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. To explain this connection, we test multiple candidate links between Ca2+ and mitochondrial homeostasis previously established in vitro, including mitochondrial calcium uniporter (MCU)-dependent stimulation of respiration and cytosolic pathways regulating mitochondrial dynamics. We find that MCU is dispensable for both respiration and longevity in Complex I mutants. Conversely, transcriptomic profiling and imaging reveal InsP3R impairment results in maladaptive expansion of compromised mitochondrial networks. We provide evidence that this aberrant mitochondrial expansion results from disruption of a conserved, InsP3R-dependent actin remodeling network centered on Arp2/3. Disruption of actin remodeling or autophagy mimics the mitochondrial expansion and longevity suppression of InsP3R mutants. Conversely, driving mitochondrial fragmentation ameliorates mitochondrial expansion and rescues longevity in InsP3R mutants, supporting a model in which InsP3R-dependent actin remodeling is required for segregation and clearance of mitochondria. These findings identify an inter-organelle signalling axis linking ER calcium release and cytoskeletal remodeling to adaptive mitochondrial responses associated with longevity.