Regulation of longevity by depolarization-induced activation of PLC-β–IP 3 R signaling in neurons

Significance We demonstrate that depolarization of Drosophila glutamatergic neurons augmented inositol trisphosphate receptor (IP 3 R)-dependent release of endoplasmic reticulum (ER) Ca 2+ , which in turn potentiated mitochondrial Ca 2+ uptake and ATP production. Perturbations that induced chronic depolarization, including the expression of neurodegeneration-related transgenes, led to the diversion of released ER Ca 2+ into lysosomes and an attendant shortening of animal lifespan. Thus, genetic disruption of PLC-β–IP 3 R signaling or lysosomal Ca 2+ uptake restored longevity in animals with chronically depolarized glutamatergic neurons. Our findings point to aberrant Ca 2+ signaling between the ER and lysosomes as a mechanism by which hyperexcitable glutamatergic neurons shorten animal lifespan.