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

Academic Article

Abstract

  • 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 inthe 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 30min. 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.
  • Authors

    Published In

  • Cell Reports  Journal
  • Digital Object Identifier (doi)

    Author List

  • Kwong JQ; Lu X; Correll RN; Schwanekamp JA; Vagnozzi RJ; Sargent MA; York AJ; Zhang J; Bers DM; Molkentin JD
  • Start Page

  • 15
  • End Page

  • 22
  • Volume

  • 12
  • Issue

  • 1