SUMO2-mediated SUMOylation of SH3GLB1 promotes ionizing radiation-induced hypertrophic cardiomyopathy through mitophagy activation

Abstract

Hypertrophic cardiomyopathy (HC) is characterized by the enlargement of individual cardiomyocytes, which is a typical pathophysiological process that occurs in various cardiovascular diseases. Ionizing radiation (IR) is an important independent risk factor for hypertrophic cardiomyopathy, but the underlying molecular mechanism is still unclear. In the present study, we aimed to clarify the role of IR in promoting cardiac hypertrophy and investigate the mechanism by which the SUMO2-mediated SUMOylation of SH3GLB1 affects mitophagy in IR-induced cardiac hypertrophy. In vivo, IR promoted cardiac hypertrophy by activating mitophagy. In vitro, IR upregulated PINK1 and Parkin protein expression and damaged mitochondrial morphological structure. We further demonstrated that SH3GLB1 deficiency inhibited mitophagy activation and restored mitochondrial cristae, revealing a regulatory role of SH3GLB1 in cardiac hypertrophy. IR promoted interactions between SH3GLB1 and mitochondrial membrane proteins, such as MFN1/2, TOM20 and Drp1, further indicating that the mechanism by which SH3GLB1 functions in cardiac hypertrophy might involve mitophagy. A bioinformatics prediction found that SUMO2 could SUMOylate SH3GLB1 at position K82. Consistent with this finding, both co-IP assays and laser confocal microscopy showed that IR promoted the interaction and colocalization of SUMO2 and SH3GLB1. In summary, our study identifies IR as an important factor that promotes hypertrophic cardiomyopathy by accelerating the activation of mitophagy through the SUMO2-mediated SUMOylation of SH3GLB1; thus, IR exerts dual therapeutic effects in the treatment of thoracic tumours with long-term radiotherapy. Additionally, this study provides novel treatment strategies and targets for preventing the hypertrophic cardiomyopathy caused by thoracic tumour radiotherapy. Furthermore, SH3GLB1 may be a promising experimental target for the development of strategies for treating cardiovascular diseases caused by IR.