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

Neeharika Nemani, Zhiwei Dong, Cassidy C. Daw, Travis R. Madaris, Karthik Ramachandran, Benjamin T. Enslow, Cherubina S. Rubannelsonkumar, Santhanam Shanmughapriya, Varshini Mallireddigari, Soumya Maity, Pragya SinghMalla, Kalimuthusamy Natarajanseenivasan, Robert Hooper, Christopher E. Shannon, Warren G. Tourtellotte, Brij B. Singh, W. Brian Reeves, Kumar Sharma, Luke Norton, Subramanya SrikantanJonathan Soboloff, Muniswamy Madesh

Research output: Contribution to journalArticle

6 Scopus citations

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 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.

Original languageEnglish (US)
Article numbereaaz6206
JournalScience signaling
Volume13
Issue number628
DOIs
StatePublished - Apr 21 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity'. Together they form a unique fingerprint.

  • Cite this

    Nemani, N., Dong, Z., Daw, C. C., Madaris, T. R., Ramachandran, K., Enslow, B. T., Rubannelsonkumar, C. S., Shanmughapriya, S., Mallireddigari, V., Maity, S., SinghMalla, P., Natarajanseenivasan, K., Hooper, R., Shannon, C. E., Tourtellotte, W. G., Singh, B. B., Reeves, W. B., Sharma, K., Norton, L., ... Madesh, M. (2020). Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity. Science signaling, 13(628), [eaaz6206]. https://doi.org/10.1126/scisignal.aaz6206