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Roles for Neuronal Excitability and Bioenergetics in the Regulation of Longevity

Weekly Seminar | Not Open to the Public
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Mitochondrial ATP production is a well-known regulator of neuronal excitability. In this talk, I will describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. I will show that depolarization increases phospholipase-Cβ (PLCβ) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLCβ activity led to greater release of endoplasmic reticulum (ER) Ca2+ via the inositol trisphosphate receptor (IP3R), which in turn, stimulated mitochondrial Ca2+ uptake and ATP synthesis. 

Expression of a gene encoding an ALS-causing variant of an ER membrane protein, VAPB, decouples mitochondrial ATP production from neuronal activity. Due to a combination of diminished ATP production and elevated ATP consumption — established outcomes in ALS neurons — the levels of ATP in mutant neurons are unable to keep up with the bioenergetic burden of depolarization. The resulting paucity of ATP results in diminished extrusion of cytosolic Ca2+, defects in synaptic vesicle release, and chronic depolarization. 

Sustained depolarization of neurons in models of ALS and tauopathy led to untrammeled PLCβ–IP3R activation, and a dramatic shortening of Drosophila lifespan. Investigation of the underlying mechanisms revealed that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLCβ/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLCβ–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.

Dr. Kartik Venkatachalam's Figure


Nicholas E. Karagas, Kai Li Tan, Hugo J. Bellen, View ORCID ProfileKartik Venkatachalam, Ching-On Wong
Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila model of ALS
bioRxiv 2021.12.14.472444.
Jewon Jung, Han Liao, Shannon A Coker, Hong Liang, John F Hancock, Catherine Denicourt, Kartik Venkatachalam
p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1
iScience. 2021 Jun 9;24(7):102701. doi: 10.1016/j.isci.2021.102701. eCollection 2021 Jul 23.
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
Regulation of longevity by depolarization-induced activation of PLC-β-IP 3 R signaling in neurons
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16):e2004253118. doi: 10.1073/pnas.2004253118.


Tuesday, January 25, 2022 - 12:30pm


Conference Room: 
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Darlene White

Conditions & Recovery

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Worldwide, 50 million people are living with Alzheimer's and other dementias.