Authors: Mingming Tong, Peiyong Zhai, Wataru Mizushima, Junichi Sadoshima
Published: 2019-10-16
DOI: 10.1161/res.125.suppl_1.284
Source: Full article
Type II diabetes induces cardiomyopathy characterized by hypertrophy, diastolic dysfunction and mitochondrial dysfunction. We have shown recently that clearance of damaged mitochondria by mitophagy mediated through an Atg7-dependent mechanism serves as an essential mechanism to maintain the quality of mitochondria during the initial development of diabetic cardiomyopathy. Our previous study showed that disruption of Drp1 inhibits mitophagy and causes mitochondrial dysfunction at baseline and in response to pressure overload. We therefore investigated whether Drp1 is essential for mitophagy during high fat diet (HFD)-induced diabetic cardiomyopathy. Mice were fed either a normal diet (ND) or a HFD (60 kcal % fat). Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD (p<0.05). However, this increase in mitophagy induced by HFD consumption was abolished in tamoxifen-inducible cardiac-specific Drp1 knockout (Drp1 cKO) mouse hearts (p<0.05), in which both diastolic dysfunction (p<0.05) and systolic dysfunction (p<0.05) were exacerbated. Furthermore, the increase in LC3-dependent general autophagy in response to HFD consumption was also abolished in Drp1 cKO mice (p<0.05). Electron microscopic analyses showed elongated mitochondria and accumulation of lipid droplets in Drp1 cKO mice (p<0.05) in the presence of HFD consumption. Fibrosis and cell death were increased in Drp1 cKO mice during HFD consumption (p<0.05). Thus, Drp1 is essential for mitophagy during HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against diabetic cardiomyopathy.