Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation

• Published in: Science signaling 2018-12, Vol.11 (560)
• Main Authors: Sato, Priscila Y, Chuprun, J Kurt, Grisanti, Laurel A, Woodall, Meryl C, Brown, Brett R, Roy, Rajika, Traynham, Christopher J, Ibetti, Jessica, Lucchese, Anna M, Yuan, Ancai, Drosatos, Konstantinos, Tilley, Doug G, Gao, Erhe, Koch, Walter J
• Format: Article
• Language: English
• Subjects: Alanine - chemistry; Alanine - genetics; Alanine - metabolism; Animal models; Animals; Apoptosis; b-Adrenergic-receptor kinase; Cardiac function; Cardiomyocytes; Cell death; Cell survival; Electron transport; Extracellular signal-regulated kinase; G protein-coupled receptors; G-Protein-Coupled Receptor Kinase 2 - genetics; G-Protein-Coupled Receptor Kinase 2 - metabolism; Glucose; Glucose - chemistry; Heart; Heart diseases; Heart failure; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - prevention & control; Injury prevention; Ischemia; Ischemia - physiopathology; Kinases; Localization; Male; Metabolism; Mice; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mortality; Myocardial infarction; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Necrosis; Oxidation; Oxidation-Reduction; Oxygen Consumption; Pathogenesis; Phosphorylation; Point Mutation; Proteins; Pyruvic acid; Receptors; Reperfusion; Respiratory function; Rodents; Serine - chemistry; Serine - genetics; Serine - metabolism; Signal Transduction; Translocation
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.aau0144

Increased abundance of GRK2 [G protein-coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes cell death. Here, we showed that mice with a S670A knock-in mutation in endogenous GRK2 showed reduced cardiomyocyte death and better cardiac function post-IR injury. Cultured GRK2-S670A knock-in cardiomyocytes subjected to IR in vitro showed enhanced glucose-mediated mitochondrial respiratory function that was partially due to maintenance of pyruvate dehydrogenase activity and improved glucose oxidation. Thus, we propose that mitochondrial GRK2 plays a detrimental role in cardiac glucose oxidation post-injury.