Regulation of longevity by depolarization-induced activation of PLC-β–IP <sub>3</sub> R 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
Abstract
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.