GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid-mediated oxygen consumption and increasing superoxide levels.
The G protein-coupled receptor kinase-2 (GRK2) is upregulated in the injured heart and contributes to heart failure pathogenesis. GRK2 was recently shown to associate with mitochondria but its functional impact in myocytes due to this localization is unclear. This study was undertaken to determine the effect of elevated GRK2 on mitochondrial respiration in cardiomyocytes. Sub-fractionation of purified cardiac mitochondria revealed that basally GRK2 is found in multiple compartments. Overexpression of GRK2 in mouse cardiomyocytes resulted in an increased amount of mitochondrial-based superoxide. Inhibition of GRK2 increased oxygen consumption rates and ATP production. Moreover, fatty acid oxidation was found to be significantly impaired when GRK2 was elevated and was dependent on the catalytic activity and mitochondrial localization of this kinase. Our study shows that independent of cardiac injury, GRK2 is localized in the mitochondria and its kinase activity negatively impacts the function of this organelle by increasing superoxide levels and altering substrate utilization for energy production.
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Priscila Y
PY
Sato
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
J Kurt
JK
Chuprun
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Jessica
J
Ibetti
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Alessandro
A
Cannavo
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Konstantinos
K
Drosatos
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
John W
JW
Elrod
Center for Translational Medicine & Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: Walter.Koch@temple.edu.
Walter J
WJ
Koch
D000818:Animals; D019069:Cell Respiration; D005227:Fatty Acids / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010101:Oxygen Consumption; D013312:Stress, Physiological; D013481:Superoxides / Q000378:metabolism*
D005227:Fatty Acids; D013481:Superoxides; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2
Cardiomyocytes; GRK2; Mitochondria; Respiration