The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart

Jennifer Q. Kwong, Xiyuan Lu, Robert N. Correll, Jennifer A. Schwanekamp, Ronald J. Vagnozzi, Michelle A. Sargent, Allen J. York, Jianyi Zhang, Donald M Bers, Jeffery D. Molkentin

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

In the heart, augmented Ca<sup>2+</sup> fluxing drives contractility and ATP generation through mitochondrial Ca<sup>2+</sup> loading. Pathologic mitochondrial Ca<sup>2+</sup> overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca<sup>2+</sup> uptake is primarily mediated by the mitochondrial Ca<sup>2+</sup> uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca<sup>2+</sup> uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca<sup>2+</sup> challenge. Mice lacking Mcu inthe adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca<sup>2+</sup> levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca<sup>2+</sup> after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca<sup>2+</sup> loading underlying a"fight-or-flight" response that acutely matches cardiac workload with ATP production.

Original languageEnglish (US)
Pages (from-to)15-22
Number of pages8
JournalCell Reports
Volume12
Issue number1
DOIs
StatePublished - Jul 7 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kwong, J. Q., Lu, X., Correll, R. N., Schwanekamp, J. A., Vagnozzi, R. J., Sargent, M. A., York, A. J., Zhang, J., Bers, D. M., & Molkentin, J. D. (2015). The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. Cell Reports, 12(1), 15-22. https://doi.org/10.1016/j.celrep.2015.06.002