Ablation of mitochondrial calcium uniporter alleviates cardiac dysfunction in type 1 diabetes.

Calcium (Ca2+) enters the mitochondria primarily through the mitochondria calcium uniporter (MCU). Conflicting results have been reported regarding the role of MCU in metabolic heart disease. Therefore, we employed a cardiomyocyte-specific MCU knockout (KO) model to assess its impact on the development of diabetic cardiomyopathy (DCM). Type 1 diabetes was induced in mice through streptozotocin (STZ) injection. The study included four groups: a wild-type (WT) control, two STZ-injected groups, designated as WT-STZ and MCUKO-STZ, and a MCUKO control. WT-STZ mice developed DCM, exhibiting contractile dysfunction (assessed by echocardiography) and ventricular arrhythmias (identified via electrocardiogram). Fluorescent imaging of isolated WT-STZ myocytes revealed impaired Ca2+ homeostasis and increased reactive oxygen species (ROS) production. Histological staining of WT-STZ cardiac tissue showed cellular hypertrophy and increased apoptosis. Mitochondrial energetics was also compromised in the WT-STZ model. MCU ablation significantly improved cardiac function in MCUKO-STZ mice, which maintained normal contractile function. Both cellular and in vivo arrhythmias were ameliorated in MCUKO-STZ. MCUKO-STZ myocytes exhibited improved Ca2+ handling and lower ROS emission. Hypertrophy and apoptosis were also alleviated in this group. Additionally, mitochondrial energetics, while not reversed, exhibited a slight trend toward improvement. Our study suggests that MCU ablation attenuates DCM progression. Inhibiting MCU-dependent Ca2+ entry may serve as a potential therapeutic strategy for type 1 diabetic cardiomyopathy by preventing arrhythmogenesis and pathological remodeling.