Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression.

Mitochondrial dysfunction leads to reactive oxygen species overload, exacerbating injury in myocardial infarction (MI). As a receptor for translocases in the outer mitochondrial membrane (Tom) complex, Tom70 has an unknown function in MI, including melatonin-induced protection against MI injury. We delivered specific small interfering RNAs against Tom70 or lentivirus vectors carrying Tom70a sequences into the left ventricles of mice or to cultured neonatal murine ventricular myocytes (NMVMs). At 48 h post-transfection, the left anterior descending coronary arteries of mice were permanently ligated, while the NMVMs underwent continuous hypoxia. At 24 h after ischemia/hypoxia, oxidative stress was assessed by dihydroethidium and lucigenin-enhanced luminescence, mitochondrial damage by transmission electron microscopy and ATP content, and cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling and caspase-3 assay. At 4 weeks after ischemia, cardiac function and fibrosis were evaluated in mice by echocardiography and Masson's trichrome staining, respectively. Ischemic/hypoxic insult reduced Tom70 expression in cardiomyocytes. Tom70 downregulation aggravated post-MI injury, with increased mitochondrial fragmentation and overload. In contrast, Tom70 upregulation alleviated post-MI injury, with improved mitochondrial integrity and decreased duanyu1670 production. PGC-1α/Tom70 expression in ischemic myocardium was increased with melatonin alone, but not when combined with luzindole. Melatonin attenuated post-MI injury in control but not in Tom70-deficient mice. N-acetylcysteine (NAC) reversed the adverse effects of Tom70 deficiency in mitochondria and cardiomyocytes, but at a much higher concentration than melatonin. Our findings showed that Tom70 is essential for melatonin-induced protection against post-MI injury, by breaking the cycle of mitochondrial impairment and duanyu1670 generation.

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