DDX60 protects ischemic myocardial injury and heart dysfunction by improving mitochondrial function via promoting Arl2 mRNA translation.

Abstract

Mitochondrial dysfunction is increasingly recognized as a pivotal driver of cardiomyocyte apoptosis and cardiac deterioration following myocardial infarction (MI). This study identifies a significant upregulation of DDX60 in cardiomyocytes under hypoxic conditions. Elevated DDX60 levels enhance mitochondrial function and attenuate cardiomyocyte apoptosis in vitro, whereas its knockdown induces the opposite effects. In vivo, cardiomyocyte-specific DDX60 knockout markedly exacerbates mitochondrial dysfunction and apoptosis, accelerating post-MI cardiac remodeling and functional decline. Furthermore, we found that Arl2 knockdown partially negates the protective effects of DDX60 overexpression on ATP production and apoptosis. Conversely, adeno-associated virus-9 (AAV9)-mediated Arl2 overexpression partially restores cardiac function, reduces infarct size, and rescues mitochondrial integrity in DDX60 CKO mice post-MI. Mechanistically, DDX60 forms a translational complex with eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) that enhances Arl2 mRNA translation, a process essential for mitochondrial homeostasis. Collectively, these findings establish DDX60 as a key regulator of cardioprotection post-MI by enhancing Arl2 translation, highlighting its potential as a therapeutic target for ischemic heart disease.