Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons

Ching On Wong, Nicholas E. Karagas, Jewon Jung, Qiaochu Wang, Morgan A. Rousseau, Yufang Chao, Ryan Insolera, Pushpanjali Soppina, Catherine A. Collins, Yong Zhou, John F. Hancock, Michael X. Zhu, Kartik Venkatachalam

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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 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-β-IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β-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.

Original languageEnglish (US)
Article numbere2004253118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Apr 20 2021

All Science Journal Classification (ASJC) codes

  • General


  • Aging
  • ER Ca signaling
  • Longevity
  • Lysosomes
  • Neuronal excitability


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