title: Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo.
abstract: Ca(2+) fluxes between adjacent organelles are thought to control many cellular processes, including metabolism and cell survival. In vitro evidence has been presented that constitutive Ca(2+) flux from intracellular stores into mitochondria is required for basal cellular metabolism, but these observations have not been made in vivo. We report that controlled in vivo depletion of cardiac RYR2, using a conditional gene knock-out strategy (cRyr2KO mice), is sufficient to reduce mitochondrial Ca(2+) and oxidative metabolism, and to establish a pseudohypoxic state with increased autophagy. Dramatic metabolic reprogramming was evident at the transcriptional level via Sirt1/Foxo1/Pgc1α, Atf3, and Klf15 gene networks. Ryr2 loss also induced a non-apoptotic form of programmed cell death associated with increased calpain-10 but not caspase-3 activation or endoplasmic reticulum stress. Remarkably, cRyr2KO mice rapidly exhibited many of the structural, metabolic, and molecular characteristics of heart failure at a time when RYR2 protein was reduced 50%, a similar degree to that which has been reported in heart failure. RYR2-mediated Ca(2+) fluxes are therefore proximal controllers of mitochondrial Ca(2+), ATP levels, and a cascade of transcription factors controlling metabolism and survival.
authors.affiliation: Cardiovascular Research Group, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bround
authors.forename: Rich
authors.initials: R
authors.lastname: Wambolt
authors.forename: Dan S
authors.initials: DS
authors.lastname: Luciani
authors.forename: Jerzy E
authors.initials: JE
authors.lastname: Kulpa
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
authors.forename: Roger W
authors.initials: RW
authors.lastname: Brownsey
authors.forename: Michael F
authors.initials: MF
authors.lastname: Allard
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000860:Hypoxia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology*; D010100:Oxygen / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D000255:Adenosine Triphosphate; D010100:Oxygen; D002118:Calcium
keywords: Calcium Channels; Calcium Signaling; Cell Death; Cell Metabolism; Hypoxia; Mitochondria; Mitochondrial Metabolism; Ryanodine Receptor