title: Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart.
abstract: Myocardial mitochondrial Ca(2+) entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca(2+) are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca(2+) uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca(2+) entry in myocardium, but, surprisingly, isolated perfused hearts exhibited higher O2 consumption rates (OCR) and impaired pacing induced mechanical performance compared with wild-type (WT) littermate controls. In contrast, OCR in DN-MCU-permeabilized myocardial fibers or isolated mitochondria in low Ca(2+) were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca(2+) homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca(2+)] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca(2+) homeostasis. Mitochondrial Ca(2+) overload is thought to dissipate the inner mitochondrial membrane potential (ΔΨm) and enhance formation of reactive oxygen species (ROS) as a consequence of ischemia-reperfusion injury. Our data show that DN-MCU hearts had preserved ΔΨm and reduced ROS during ischemia reperfusion but were not protected from myocardial death compared with WT. Taken together, our findings show that chronic myocardial MCU inhibition leads to previously unanticipated compensatory changes that affect cytoplasmic Ca(2+) homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Tyler P
authors.initials: TP
authors.lastname: Rasmussen
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Mei-ling A
authors.initials: ML
authors.lastname: Joiner
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wilson
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.affiliation: Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCormick
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.affiliation: Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Nuclear Magnetic Resonance Core Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Boudreau
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.affiliation: Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; mark.anderson@jhmi.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D065150:Cellular Reprogramming; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003971:Diastole; D004562:Electrocardiography; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D011451:Prostaglandin-Endoperoxide Synthases; D005947:Glucose; D002118:Calcium
keywords: ischemia-reperfusion injury; mitochondrial calcium uniporter; myocardium