Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting prohibitin 2-Pink1-mediated mitophagy.

Ischemic heart disease is among the cardiovascular diseases with the highest mortality rates worldwide. Redox homeostasis is critical for a wide range of biological processes, including cardiac injury and repair. Methionine sulfoxide reductase A (MSRA) has been reported as a protective factor for cardiomyocytes both in vivo and in vitro, however, the underlying mechanisms are not fully understood. Here we demonstrated that Msra deficiency in zebrafish results in heart regeneration failure after larval ventricle ablation. Using a proximity labelling assay we identified prohibitin 2a (Phb2a), an ortholog of human PHB2, as a potential substrate of Msra. We further revealed that Pink1-mediated mitophagy is inhibited, thereby impairing heart regeneration in Msra-deficient zebrafish. Moreover, mitophagy is also impeded in Msra-KO HL-1 mouse cardiomyocytes under oxidative stress. Blocking the oxidation of PHB2 by substituting its essential methionine with valine rescues Msra-KO cardiomyocytes from oxidative stress. Taken together, our findings shed light on the role that methionine redox homeostasis plays in the regulation of mitophagy in ischemic heart disease and provide a foundation for the identification of novel therapeutic targets.