Young 2021 J Biol Chem

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Young MP, Schug ZT, Booth DM, Yule DI, Mikoshiba K, Hajnóczky G, Joseph SK (2021) Metabolic adaptation to the chronic loss of Ca2+ signaling induced by knockout of IP 3 receptors or the mitochondrial Ca2+ uniporter. J Biol Chem [Epub ahead of print].

» PMID: 34801549 Open Access

Young Michael P, Schug Zachary T, Booth David M, Yule David I, Mikoshiba Katsuhiko, Hajnoczky Gyoergy, Joseph Suresh K (2021) J Biol Chem

Abstract: Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum (ER) inositol trisphosphate receptors (IP3R) 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 bioenergetics 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, HeLa) with stable knockouts of all three IP3R isoforms (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 due to 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. Keywords: IP(3) receptor, TCA cycle, Bioenergetics, Calcium signaling, Glycolysis, Mitochondrial calcium uniporter, Mitochondrial metabolism Bioblast editor: Plangger M


Labels: MiParea: Respiration, Genetic knockout;overexpression 


Organism: Human  Tissue;cell: HEK, HeLa  Preparation: Intact cells 


Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

2021-11