Metabolic adaptation to the chronic loss of Ca 2+ signaling induced by KO of IP 3 receptors or the mitochondrial Ca 2+ uniporter

Authors

Michael P. Young, Thomas Jefferson UniversityFollow
Zachary T Schug, The Wistar Institute
David M. Booth, Thomas Jefferson UniversityFollow
David I Yule, University of Rochester
Katsuhiko Mikoshiba, Shanghai Tech University
György Hajnóczky, Thomas Jefferson UniversityFollow
Suresh K Joseph, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

11-19-2021

Comments

This article is the author’s final published version in Journal of Biological Chemistry, Volume 298, Issue 11, November 2021, Article number 101436.

The published version is available at https://doi.org/10.1016/j.jbc.2021.101436. Copyright © Young et al.

Abstract

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP3R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely because of adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.

Recommended Citation

Young, Michael P.; Schug, Zachary T; Booth, David M.; Yule, David I; Mikoshiba, Katsuhiko; Hajnóczky, György; and Joseph, Suresh K, "Metabolic adaptation to the chronic loss of Ca 2+ signaling induced by KO of IP 3 receptors or the mitochondrial Ca 2+ uniporter" (2021). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 339.
https://jdc.jefferson.edu/pacbfp/339

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

34801549

Language

English