title: The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition.
abstract: Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+)-dependent metabolism during acute stress.
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Luongo
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Ancai
authors.initials: A
authors.lastname: Yuan
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Cardiovascular Research, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Gross
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
authors.affiliation: Center for Cardiovascular Research, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: elrod@temple.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004734:Energy Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D013312:Stress, Physiological
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D002118:Calcium