Research ArticleCardiovascular Biology

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

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Science Signaling  11 Dec 2018:
Vol. 11, Issue 560, eaau0144
DOI: 10.1126/scisignal.aau0144

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.

Abstract

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.

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