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

Preventing GRK2 from localizing to mitochondria lessens the damage induced by myocardial infarction. Pinning GRK2 in place to protect the heart In addition to its role in terminating signaling mediated by activated G protein–coupled receptors, the kinase GRK2 also localizes to mitochondria to regulate cell survival and metabolism in a manner dependent on phosphorylation of Ser670 by ERK. Sato et al. found that mice that expressed a mutant form of GRK2 that could not undergo this phosphorylation event showed decreased mitochondrial accumulation of the mutant GRK2, reduced cardiac necrosis, and improved cardiac function after ischemia-reperfusion injury. Compared to those from wild-type mice, cardiomyocytes from mice expressing the nonphosphorylatable form of GRK2 were better able to maintain a normal metabolism when subjected to ischemia-reperfusion injury in vitro. These results show that preventing GRK2 from translocating to mitochondria after myocardial infarction is cardioprotective. 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 Ser670 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.