Research ArticleMetabolism

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

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Science Signaling  21 Apr 2020:
Vol. 13, Issue 628, eaaz6206
DOI: 10.1126/scisignal.aaz6206

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Rheostat for mitochondrial Ca2+ uptake during stress

Ca2+ entering mitochondria through the mitochondrial Ca2+ uniporter (MCU) normally promotes the generation of ATP through the TCA cycle. Nemani et al. found that nutrient stress initiated a transcriptional program that restricted Ca2+ influx into mitochondria through the MCU to prevent changes in mitochondrial dynamics and bioenergetics. Pharmacological or genetic disruptions in glycolysis or uptake of pyruvate or fatty acids induced the transcription factor EGR1 to increase the expression of the gene encoding MICU1, a gatekeeper for the MCU, resulting in reduced mitochondrial Ca2+ uptake. The authors propose that this response prevents mitochondria from becoming overloaded with Ca2+ and limits bioenergetics crises during nutrient stress.


The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH2. Although mitochondrial matrix uptake of Ca2+ enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca2+ flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca2+, 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 MPC1R97W resulted in increased MICU1 protein abundance and inhibition of MCU-mediated mitochondrial matrix uptake of Ca2+. We also found that genetic ablation of MPC1 in hepatocytes and mouse embryonic fibroblasts resulted in reduced resting matrix Ca2+, likely because of increased MICU1 expression, but resulted in changes in mitochondrial morphology. TCA cycle substrate–dependent MICU1 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 Ca2+ 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 Ca2+ overload during periods of nutrient stress.

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