posted on 2019-03-08, 13:51authored byPriscila Y. Sato, J. Kurt Chuprun, Laurel A. Grisanti, Meryl C. Woodall, Brett R. Brown, Rajika Roy, Christopher J. Traynham, Jessica Ibetti, Anna M. Lucchese, Ancai Yuan, Konstantinos Drostatos, Douglas G. Tilley, Erhe Gao, Walter J. Koch
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.