Mrps15/Mrps21 induced by Zhx1 protects mice from hypertensive heart disease by restoring mitochondrial translation

Mitochondria and mitochondrial proteins represent attractive pharmacological candidates in the search for novel molecular targets to counteract the onset of hypertensive heart disease (HHD). In this work, we aimed to dissect the role and mechanism of mitochondrial ribosomal protein S21 (Mrps21) and Mrps15 in modulating mitochondrial dysfunction during HHD. Mrps15/Mrps21 expression was reduced in myocardial tissues of HHD mice induced by a 5-week gavage of L-NAME (70 mg/kg). Knockdown of Mrps15/Mrps21 inhibited mitochondrial translation in cardiomyocytes, which resulted in depolarization of mitochondrial membrane potential, impaired mitochondrial respiration, reduced membrane translocation of nuclear-encoded mitochondrial proteins, and mitochondrial reactive oxygen species production associated with reduced mitochondrial glutaredoxin-2. Mrps15/Mrps21 ameliorated myocardial injury associated with mitochondrial translation, thereby restoring cardiac function in mice. Zinc fingers and homeoboxes protein 1 (Zhx1) promoted the transcription of Mrps15/Mrps21. Zhx1 activator mithramycin treatment or Zhx1 overexpression ameliorated mitochondrial damage in HHD mice and L-NAME/Ang Ⅱ-stimulated cardiomyocytes, whereas combined silencing of Mrps15/Mrps21 compromised the protective effect of Zhx1 on cardiomyocytes. Our results demonstrate that Zhx1-mediated activation of Mrps15/Mrps21 transcription inhibits HHD progression through the mitochondrial pathway, and a potential therapeutic strategy for the clinical management of HHD is represented by pharmacological activation of Zhx1.