Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity

The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH Although mitochondrial matrix uptake of Ca enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochon...

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Published in:	Science signaling Vol. 13; no. 628
Main Authors:	Nemani, Neeharika, Dong, Zhiwei, Daw, Cassidy C, Madaris, Travis R, Ramachandran, Karthik, Enslow, Benjamin T, Rubannelsonkumar, Cherubina S, Shanmughapriya, Santhanam, Mallireddigari, Varshini, Maity, Soumya, SinghMalla, Pragya, Natarajanseenivasan, Kalimuthusamy, Hooper, Robert, Shannon, Christopher E, Tourtellotte, Warren G, Singh, Brij B, Reeves, W Brian, Sharma, Kumar, Norton, Luke, Srikantan, Subramanya, Soboloff, Jonathan, Madesh, Muniswamy
Format:	Journal Article
Language:	English
Published:	United States 21-04-2020
Subjects:	Animals Biological Transport, Active - genetics Calcium Channels - genetics Calcium Channels - metabolism Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cation Transport Proteins - genetics Cation Transport Proteins - metabolism Fatty Acids - metabolism HEK293 Cells HeLa Cells Hep G2 Cells Humans Mice, Knockout Mitochondria, Liver - genetics Mitochondria, Liver - metabolism Mitochondrial Membrane Transport Proteins - genetics Mitochondrial Membrane Transport Proteins - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Pyruvic Acid - metabolism
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Summary:	The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH Although mitochondrial matrix uptake of Ca enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca , mitochondrial bioenergetics, and autophagic flux. Inhibition of glycolysis, mitochondrial pyruvate transport, or mitochondrial fatty acid transport triggered expression of the MCU gatekeeper MICU1 but not the MCU core subunit. Knockdown of mitochondrial pyruvate carrier (MPC) isoforms or expression of the dominant negative mutant MPC1 resulted in increased MICU1 protein abundance and inhibition of MCU-mediated mitochondrial matrix uptake of Ca We also found that genetic ablation of MPC1 in hepatocytes and mouse embryonic fibroblasts resulted in reduced resting matrix Ca , likely because of increased expression, but resulted in changes in mitochondrial morphology. TCA cycle substrate-dependent expression was mediated by the transcription factor early growth response 1 (EGR1). Blocking mitochondrial pyruvate or fatty acid flux was linked to increased autophagy marker abundance. These studies reveal a mechanism that controls the MCU-mediated Ca flux machinery and that depends on TCA cycle substrate availability. This mechanism generates a metabolic homeostatic circuit that protects cells from bioenergetic crisis and mitochondrial Ca overload during periods of nutrient stress.
ISSN:	1937-9145
DOI:	10.1126/scisignal.aaz6206