期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2004253118
关键词
longevity; aging; ER Ca2+ signaling; lysosomes; neuronal excitability
资金
- NIH [RF1AG069076, R21AG067414]
Mitochondrial ATP production plays a crucial role in regulating neuronal excitability, and the influence of plasma-membrane potential on ATP production is significant. Depolarized neurons can elevate the ATP/ADP ratio through increased PLC-beta-IP3R signaling, but excessive activation of this pathway leads to a shortened lifespan in Drosophila.
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-C beta (PLC-beta) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-beta activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-beta-IP3R activation and a dramatic shortening of Drosophila life-span. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP(3)Rs. Manipulations that either lowered PLC-beta/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-beta-IP3R 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 Ca2+ overload.
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