title: The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.
abstract: In the heart, augmented Ca(2+) fluxing drives contractility and ATP generation through mitochondrial Ca(2+) loading. Pathologic mitochondrial Ca(2+) overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca(2+) uptake is primarily mediated by the mitochondrial Ca(2+) uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca(2+) uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca(2+) challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca(2+) levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca(2+) 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 Ca(2+) loading underlying a "fight-or-flight" response that acutely matches cardiac workload with ATP production.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Kwong
authors.affiliation: Department of Pharmacology, University of California-Davis, Davis, CA 95616, USA.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Correll
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schwanekamp
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: York
authors.affiliation: Department of Medicine, Leilihei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of California-Davis, Davis, CA 95616, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA; Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D013312:Stress, Physiological
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D000255:Adenosine Triphosphate; D002118:Calcium