title: The mitochondrial uniporter controls fight or flight heart rate increases.
abstract: Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1] Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA [2] Department of Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Tyler P
authors.initials: TP
authors.lastname: Rasmussen
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Mei-Ling A
authors.initials: ML
authors.lastname: Joiner
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Hall
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1] Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA [2] Department of Internal Medicine II, University Hospital Regensburg, 93042 Regensburg, Germany.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Rokita
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.affiliation: 1] Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA [2] Department of Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001683:Biological Clocks; D002110:Caffeine / Q000737:chemistry; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D004452:Echocardiography / Q000379:methods; D004562:Electrocardiography / Q000379:methods; D005260:Female; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006321:Heart / Q000502:physiology; D006339:Heart Rate / Q000502:physiology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000737:chemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D009243:NAD / Q000737:chemistry; D010477:Perfusion; D010766:Phosphorylation; D019076:Transgenes
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D009243:NAD; D049452:Green Fluorescent Proteins; D002110:Caffeine; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D002118:Calcium