title: Mitochondrial calcium overload is a key determinant in heart failure.
abstract: Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca2+ is essential for optimal function of these organelles. However, Ca2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ overload and dysfunction in HF.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; gsantulli001@gmail.com arm42@cumc.columbia.edu.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032;
authors.forename: Wenjun
authors.identifier: http://orcid.org/0000-0003-0493-062X
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032;
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032; Department of Medicine, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032 gsantulli001@gmail.com arm42@cumc.columbia.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism*; D015151:Immunoblotting; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: IP3 receptor; calcium; heart failure; mitochondria; ryanodine receptor