Myocardial-specific GRK2 knockout induces cardiac and mitochondrial dysfunction in response to ionizing radiation exposure

Radiation-induced heart disease is a complication of radiotherapy, caused by mitochondrial dysfunction and oxidative stress. G protein-coupled receptor kinase 2 (GRK2), beyond its typical role in G protein-coupled receptors desensitization, has been linked to mitochondrial dynamics and cardiomyocyte health. We studied the effects of ionizing radiation (IR) exposure in cardiomyocyte-specific GRK2 knockout (Myh-GRK2 KO) mice compared with GRK2flox/flox (control, CTR) at 3 h and 24 h post-IR. GRK2 deficiency worsens IR-induced cardiac dysfunction at 3 h postexposure, persisting at 24 h. Proteomic analysis showed that GRK2 deficiency impairs the expression of mitochondrial proteins basally. Transmission electron microscopy showed a reduction in mitochondrial number, increased swelling, and an altered structure in Myh-GRK2 KO mice. Importantly, GRK2 deficiency impaired activation of the PINK1/Parkin/dynamin-related protein 1 mitophagy axis, while increasing light chain 3 and decreasing p62 levels. In CTR mice, GRK2 moved to mitochondria post-IR, supporting mitochondrial integrity. GRK2 is essential for mitochondrial integrity during IR stress; its absence induces mitochondrial alterations, impairs mitophagy, and leads to cardiac dysfunction, identifying GRK2 as a therapeutic target.NEW & NOTEWORTHY Acute ionizing radiation rapidly impairs cardiac mitochondrial homeostasis and function. Cardiomyocyte-specific deletion of GRK2 markedly worsens early radiation-induced cardiac dysfunction. Loss of GRK2 disrupts mitochondrial quality control, reducing activation of the PINK1/Parkin/DRP1 mitophagy pathway and increasing mitochondrial damage. Following irradiation, GRK2 translocates to mitochondria and supports mitochondrial integrity and stress responses. These findings highlight an unrecognized protective role of mitochondrial GRK2 in the early cardiac response to ionizing radiation exposure.