Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo

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 (c Ryr2 KO 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 / Pgc1 α, 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, c Ryr2 KO 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. Background: Intracellular Ca 2+ release has been implicated in ATP production in vitro . Results: In vivo deletion of Ryr2 reduces Ca 2+ , ATP, and oxidative metabolism, leading to metabolic reprogramming and cell death. Conclusion: RYR2 maintains cardiomyocyte ATP production and survival in vivo . Significance: This work links heart metabolism to function via Ca 2+ release from intracellular stores.