Protective roles of MITOL in ischemic heart disease and heart failure with aging partly via Drp1 regulation Takeshi Tokuyama1, Shigeru Yanagi1 1Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Accumulating evidence indicates that mitochondrial dysfunction is an important contributor to both ischemic heart disease and development of heart failure with aging phenotype. However, the molecular mechanism underlying mitochondrial dysfunction is not fully understood.
We previously identified mitochondrial ubiquitin ligase MITOL (also known as MARCH5), and demonstrated that MITOL promotes dynamin-related protein 1 (Drp1) degradation through the ubiquitin-proteasome pathway, thereby inhibiting excessive accumulation of Drp1 on mitochondria in cultured cells. Here we show that MITOL is involved in the pathology of ischemic heart disease and heart failure with aging. We found that MITOL was rapidly down-regulated in hearts of a rat model and human patients of myocardial infarction (MI). Indeed, mitochondrial fragmentation by accumulated Drp1 was observed in heart of rat MI model. Excitingly, fibrosis and cardiac dysfunction of rat MI model were significantly rescued by adeno-associated virus 9-mediated MITOL expression. These results suggest that enhanced Drp1 toxicity by MITOL dysfunction is closely involved in the pathology of ischemic heart disease and that MITOL is therapeutic target for ischemic heart disease.
We next examined the physiological relevance of MITOL in cardiac function. For this purpose, we generated tamoxifen-inducible cardiomyocyte-specific conditional knockout of MITOL in mice. Cardiac-specific deletion of MITOL caused Drp1 accumulation in mitochondria and disrupted mitochondrial morphology, resulting in severe mitochondrial damage such as ROS production. Treatment of Mdivi-1, a Drp1 inhibitor, partially rescued mitochondrial morphological change and damage. After 6 months from MITOL deletion, mutant mice exhibited severe heart failure with accelerated aging phenotype and died within one year. These results demonstrate that MITOL is essential for maintenance of normal cardiac function and protects against heart failure and aging, at least in part, through Drp1 regulation.