Regulation of longevity by depolarization-induced activation of PLC-β-IPR 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 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 via the inositol trisphosphate receptor (IPR), increased mitochondrial Ca uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β-IPR activation and a dramatic shortening of lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca into endolysosomes was an intermediary in the regulation of lifespan by IPRs. Manipulations that either lowered PLC-β/IPR abundance or attenuated endolysosomal Ca overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β-IPR 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 overload.