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:10.1016/j.celrep.2015.06.002

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

Affiliations

Jennifer Q. Kwong: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Xiyuan Lu: Department of Pharmacology, University of California-Davis, Davis, CA 95616, USA
Robert N. Correll: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Jennifer A. Schwanekamp: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Ronald J. Vagnozzi: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Michelle A. Sargent: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Allen J. York: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
Jianyi Zhang: Department of Medicine, Leilihei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA
Donald M. Bers: Department of Pharmacology, University of California-Davis, Davis, CA 95616, USA
Jeffery D. Molkentin: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA

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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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