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“Roles for neuronal excitability and bioenergetics...
Pharmacology & Chemical Biology Seminar Series
3/3/2022 - 12:00 PM-1:00 PM
“Roles for neuronal excitability and bioenergetics in the regulation of longevity.”
Kartik Venkatachalam, Ph.D.
Associate Professor
McGovern Medical School
part of UTHealth | The University of Texas Health Science Center at Houston
Department of Integrative Biology and Pharmacology
Mitochondrial ATP production is a well-known regulator of neuronal excitability. In this talk, I will describe a mechanism by which neurons deal with the bioenergetic burden depolarization by potentiating ER calcium release that drives mitochondrial ATP production. In models of neurodegeneration, a combination of diminished ATP production and elevated ATP consumption, 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 Ca
2+
, defects in synaptic vesicle release, and chronic depolarization.
Sustained depolarization of neurons in
Drosophila
models of ALS and tauopathy led to a dramatic shortening of
Drosophila
lifespan. Investigation of the underlying mechanisms revealed roles for untrammeled ER calcium release, and increased sequestration of the calcium into endolysosomes. Manipulations that either lowered ER calcium release or attenuated endolysosomal calcium overload restored animal longevity. Collectively, the findings I will describe demonstrate that depolarization modulates ATP production in healthy glutamatergic neurons, whereas in models of neurodegeneration, chronic depolarization of glutamatergic neurons shortens animal lifespan by promoting endolysosomal calcium overload.
Contact
Melanie Hoffner