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

Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity. Sci Signal. 2020 Apr 21;13(628): Authors: Nemani N, Dong Z, Daw CC, Madaris TR, Ramachandran K, Enslow BT, Rubannelsonkumar CS, Shanmughapriya S, Mallireddigari V, Maity S, SinghMalla P, Natarajanseenivasan K, Hooper R, Shannon CE, Tourtellotte WG, Singh BB, Reeves WB, Sharma K, Norton L, Srikantan S, Soboloff J, Madesh M Abstract 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 in...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research