MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca 2+ –Dependent Antioxidant Response

Diabetic cardiomyopathy is a major cause of mortality in diabetic patients, but specific strategies for prevention or treatment of diabetic cardiomyopathy have not been clarified yet. MICU1 is a key regulator of mitochondria Ca(2+) uptake, which plays important roles in regulating mitochondrial oxidative phosphorylation and redox balance. However, to date, the significance of MICU1 in diabetic hearts has never been investigated. Here, we demonstrated that MICU1 was downregulated in db/db mouse heart, which contributes to myocardial apoptosis in diabetes. Importantly, the reconstitution of MICU1 in diabetic hearts significantly inhibited the development of diabetic cardiomyopathy as evidenced by enhanced cardiac function, reduced cardiac hypertrophy and myocardial fibrosis in db/db mice. Moreover, our in vitro data showed that the reconstitution of MICU1 inhibited the apoptosis of cardiomyocytes induced by high glucose and high fat through increasing mitochondrial Ca(2+) uptake and subsequently activating the antioxidant system. Finally, our results indicated that hyperglycemia and hyperlipidemia induced the downregulation of MICU1 via inhibiting Sp1 expression in diabetic cardiomyocytes. Collectively, our findings provide the first direct evidence that upregulated MICU1 preserves cardiac function in diabetic db/db mice, suggesting that increasing the expression or activity of MICU1 may be a pharmacological approach to ameliorate cardiomyopathy in diabetes.