(P22-024-25) Ablation of Mitochondrial Calcium Uniporter Alleviated Pathophenotype in a Mouse Model of Diabetic Cardiomyopathy by Inhibition of ROS Production

Objectives: Calcium (Ca) 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 test the hypothesis that MCU ablation will slow the development of type 1 diabetes.

Methods: Type I diabetes was induced by injecting the mice with streptozotocin (STZ). In vivo cardiac function was assessed by echocardiography and electrocardiogram. Myocytes were isolated from mice hearts to measure intra-cellular Ca dynamics and ROS emission, using fluorescent microscopy. Histological staining of the fixed heart tissue was performed to examine apoptosis and cellular hypertrophy. Mitochondrial respiratory function was analyzed by high-resolution respirometry.

Results: The study included three groups: the wild-type (WT) control, and two groups of mice undergoing STZ injection, denoted as WT-STZ and MCUKO-STZ. WT-STZ developed DCM pathophenotype, exhibiting in vivo contractile dysfunction measured by echocardiography, and ventricular arrhythmias identified by electrocardiogram. Fluorescent imaging of isolated WT-STZ myocytes shows impaired myocyte Ca homeostasis and increased ROS production. Histological staining of WT-STZ tissue revealed cellular hypertrophy and increased apoptosis. Mitochondrial metabolic function was also compromised in the WT-STZ model. Ablation of MCU significantly improved in vivo cardiac function, MCUKO-STZ mice exhibited normal contractile function. Myocytes of MCUKO-STZ had improved Ca handling and reduced ROS emission. Both cellular arrhythmias and in vivo arrhythmias were ameliorated in the MCUKO-STZ. Hypertrophy and apoptosis were also reversed in this group. Additionally, mitochondrial metabolic function showed a trend towards improvement. The beneficial effect of MCU ablation is likely due to the reduced ROS emission in the MCUKO-STZ myocytes. One way ANOVA was employed for statistical analyses.

Conclusions: Ablation of MCU slowed the progression DCM by reducing oxidative stress. Inhibition of MCU-dependent Ca entry is potentially therapeutic in type I diabetes by inhibiting arrhythmogenesis and pathological remodeling.

Funding Sources: This work was funded by NIH grants R15HL154073A1 and R01HL166169-01A1.