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

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca(2+) via the inositol trisphosphate receptor (IP(3)R), increased mitochondrial Ca(2+) uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP(3)R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca(2+) into endolysosomes was an intermediary in the regulation of lifespan by IP(3)Rs. Manipulations that either lowered PLC-β/IP(3)R abundance or attenuated endolysosomal Ca(2+) overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP(3)R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca(2+) overload.