MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca2+–Dependent Antioxidant Response

Abstract

Diabetic cardiomyopathy is a major cause of mortality in patients with diabetes, but specific strategies for preventing or treating diabetic cardiomyopathy have not been clarified yet. MICU1 is a key regulator of mitochondrial Ca uptake, which plays important roles in regulating mitochondrial oxidative phosphorylation and redox balance. To date, however, the significance of MICU1 in diabetic hearts has not been investigated. Here, we demonstrate that MICU1 was downregulated in mouse hearts, 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 and reduced cardiac hypertrophy and myocardial fibrosis in mice. Moreover, our in vitro data show that the reconstitution of MICU1 inhibited the apoptosis of cardiomyocytes, induced by high glucose and high fat, through increasing mitochondrial Ca uptake and subsequently activating the antioxidant system. Finally, our results indicate that hyperglycemia and hyperlipidemia induced the downregulation of MICU1 by inhibiting Sp1 expression in diabetic cardiomyocytes. Collectively, our findings provide the first direct evidence that upregulated MICU1 preserves cardiac function in diabetic mice, suggesting that increasing the expression or activity of MICU1 may be a pharmacological approach to ameliorate cardiomyopathy in diabetes.

Mitochondrial dysfunction in pathophysiology of heart failure

“…In contrast, another study suggests that increased activity of mitochondrial Na + /Ca 2+ exchange in a hamster heart failure model results in decreased mitochondrial matrix Ca 2+ , impaired energy supply, and increased myocyte death (107). In models of diabetic cardiomyopathy, measures that increase mitochondrial Ca 2+ level appear to be beneficial, which argues against the Ca 2+ overload hypothesis (108,109). Mitochondrial Ca 2+ uptake is also reduced in human myocardium from explanted end-stage failing hearts (110).…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…This can impede key steps in the TCA cycle and in turn limit the supply of electrons to the respiratory complexes and lead to a shortfall in ATP synthesis . In the d b /d b mouse heart a key component of the MCU (MICU1) was reported to be downregulated, whereas targeting mitochondrial Ca 2+ uptake by overexpression of MICU1 rescued cardiac function, lowered mitochondrial ROS, improved the NADPH antioxidant system and resulted in less apoptosis mediated by oxidative stress in these diabetic hearts. Mice with streptozotocin‐induced diabetes also exhibited reduced mitochondrial Ca 2+ , and restoration of the Ca 2+ concentration by MCU overexpression in this model resulted in increased PDC activity, a shift in metabolism towards glucose oxidation, and improved mitochondrial membrane potential and respiratory efficiency .…”

Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

“…6B). In addition, ATP production in isolated mitochondria assessed by the 2-deoxy-D-glucose (2DG) ATP energy clamp method (37) demonstrated that reduced ATP production in mitochondria from diabetic hearts was increased after MCU expression, despite persistent diabetes (Fig. 6C).…”