TY - JOUR
T1 - Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons
AU - Wong, Ching On
AU - Karagas, Nicholas E.
AU - Jung, Jewon
AU - Wang, Qiaochu
AU - Rousseau, Morgan A.
AU - Chao, Yufang
AU - Insolera, Ryan
AU - Soppina, Pushpanjali
AU - Collins, Catherine A.
AU - Zhou, Yong
AU - Hancock, John F.
AU - Zhu, Michael X.
AU - Venkatachalam, Kartik
N1 - Funding Information:
We thank the Bloomington Drosophila Stock Center for fly stocks and the following investigators for sending us fly lines: Dr. Gregory Macleod, Dr. Hugo Bellen, and Dr. Leslie Griffith. We also thank Steven Gregory, Greg Boyle, and Hongxiang Hu for technical help and Drs. Ghislain Breton and Jeffrey Chang for use of equipment. Confocal and live-cell microscopy was performed at the Center for Advanced Microscopy, Department of Integrative Biology and Pharmacology at McGovern Medical School, University of Texas Health Sciences Center, Houston (UTHealth). We are grateful to Drs. Hugo Bellen, Kai-Li Tan, Dongxue Mao, Gregory Macleod, Wan Hee Yoon, Ilya Levental, Darren Boehning, Hamed Jafar-Nejad, and Marco Sardiello for helpful discussions. This work was supported by the NIH grants RF1AG069076 and R21AG067414 (to K.V.).
Funding Information:
ACKNOWLEDGMENTS. We thank the Bloomington Drosophila Stock Center for fly stocks and the following investigators for sending us fly lines: Dr. Gregory Macleod, Dr. Hugo Bellen, and Dr. Leslie Griffith. We also thank Steven Gregory, Greg Boyle, and Hongxiang Hu for technical help and Drs. Ghislain Breton and Jeffrey Chang for use of equipment. Confocal and live-cell microscopy was performed at the Center for Advanced Microscopy, Department of Integrative Biology and Pharmacology at McGovern Medical School, University of Texas Health Sciences Center, Houston (UTHealth). We are grateful to Drs. Hugo Bellen, Kai-Li Tan, Dongxue Mao, Gregory Macleod, Wan Hee Yoon, Ilya Levental, Darren Boehning, Hamed Jafar-Nejad, and Marco Sardiello for helpful discussions. This work was supported by the NIH grants RF1AG069076 and R21AG067414 (to K.V.).
Publisher Copyright:
© This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
PY - 2021/4/20
Y1 - 2021/4/20
N2 - 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.
AB - 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.
KW - Aging
KW - ER Ca signaling
KW - Longevity
KW - Lysosomes
KW - Neuronal excitability
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U2 - 10.1073/pnas.2004253118
DO - 10.1073/pnas.2004253118
M3 - Article
C2 - 33859040
AN - SCOPUS:85104412249
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
M1 - e2004253118
ER -