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

  • Author(s): Kwong, JQ
  • Lu, X
  • Correll, RN
  • Schwanekamp, JA
  • Vagnozzi, RJ
  • Sargent, MA
  • York, AJ
  • Zhang, J
  • Bers, DM
  • Molkentin, JD
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497842/
No data is associated with this publication.
Abstract

© 2015 The Authors. 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.

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