| Autor: |
Ching-On Wong, Karagas, Nicholas E., Jewon Jung, Qiaochu Wang, Rousseau, Morgan A., Yufang Chao, Insolera, Ryan, Soppina, Pushpanjali, Collins, Catherine A., Yong Zhou, Hancock, John F., Zhu, Michael X., Venkatachalam, Kartik |
| Předmět: |
|
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 4/20/2021, Vol. 118 Issue 16, p1-9, 9p |
| Abstrakt: |
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-Cß (PLC-ß) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-ß 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-ß-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-ß/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-ß-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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
