Format

Send to

Choose Destination
Sci Signal. 2018 Dec 11;11(560). pii: eaau0144. doi: 10.1126/scisignal.aau0144.

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

Author information

1
Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
2
Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
3
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
4
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
5
Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. walter.koch@temple.edu.

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.

PMID:
30538174
PMCID:
PMC6463290
[Available on 2019-06-11]
DOI:
10.1126/scisignal.aau0144

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center