Cell Reports (Jul 2015)

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

DOI
https://doi.org/10.1016/j.celrep.2015.06.002
Journal volume & issue
Vol. 12, no. 1
pp. 15 – 22

Abstract

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In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca2+ after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30 min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca2+ loading underlying a “fight-or-flight” response that acutely matches cardiac workload with ATP production.