Myocardial-Specific GRK2 knock-out induces cardiac and mitochondrial dysfunction in response to ionizing radiation exposure

Background: Radiation-induced heart disease (RIHD) 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 (GPCRs) desensitization, has been linked to mitochondrial dynamics and cardiomyocyte health. We studied the effects of IR exposure in cardiomyocyte-specific GRK2 knockout (Myh-GRK2 KO) mice compared to GRK2 fl/fl (CTR) at 3 h and 24 h post-IR. GRK2 deficiency worsens IR-induced cardiac dysfunction at 3 h post-exposure, persisting at 24 h. Proteomic analysis showed that GRK2 deficiency impairs the expression of mitochondrial proteins basally. TEM 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/DRP1 mitophagy axis, while increasing LC3 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.