Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy

粒体自噬 品脱1 线粒体分裂 自噬 心肌病 内科学 帕金 线粒体 VDAC1型 内分泌学 DNM1L型 第一季 生物 细胞生物学 医学 线粒体融合 线粒体DNA 心力衰竭 生物化学 细胞凋亡 大肠杆菌 细菌外膜 疾病 基因 帕金森病
作者
Mingming Tong,Risa Mukai,Satvik Mareedu,Peiyong Zhai,Shinichi Oka,Chun‐Yang Huang,Chiao‐Po Hsu,Fawad A. K. Yousufzai,Luke Fritzky,Wataru Mizushima,Gopal J. Babu,Junichi Sadoshima
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:133 (1): 6-21 被引量:19
标识
DOI:10.1161/circresaha.123.322512
摘要

Obesity induces cardiomyopathy characterized by hypertrophy and diastolic dysfunction. Whereas mitophagy mediated through an Atg7 (autophagy related 7)-dependent mechanism serves as an essential mechanism to maintain mitochondrial quality during the initial development of obesity cardiomyopathy, Rab9 (Ras-related protein Rab-9A)-dependent alternative mitophagy takes over the role during the chronic phase. Although it has been postulated that DRP1 (dynamin-related protein 1)-mediated mitochondrial fission and consequent separation of the damaged portions of mitochondria are essential for mitophagy, the involvement of DRP1 in mitophagy remains controversial. We investigated whether endogenous DRP1 is essential in mediating the 2 forms of mitophagy during high-fat diet (HFD)-induced obesity cardiomyopathy and, if so, what the underlying mechanisms are.Mice were fed either a normal diet or an HFD (60 kcal %fat). Mitophagy was evaluated using cardiac-specific Mito-Keima mice. The role of DRP1 was evaluated using tamoxifen-inducible cardiac-specific Drp1knockout (Drp1 MCM) mice.Mitophagy was increased after 3 weeks of HFD consumption. The induction of mitophagy by HFD consumption was completely abolished in Drp1 MCM mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. The increase in LC3 (microtubule-associated protein 1 light chain 3)-dependent general autophagy and colocalization between LC3 and mitochondrial proteins was abolished in Drp1 MCM mice. Activation of alternative mitophagy was also completely abolished in Drp1 MCM mice during the chronic phase of HFD consumption. DRP1 was phosphorylated at Ser616, localized at the mitochondria-associated membranes, and associated with Rab9 and Fis1 (fission protein 1) only during the chronic, but not acute, phase of HFD consumption.DRP1 is an essential factor in mitochondrial quality control during obesity cardiomyopathy that controls multiple forms of mitophagy. Although DRP1 regulates conventional mitophagy through a mitochondria-associated membrane-independent mechanism during the acute phase, it acts as a component of the mitophagy machinery at the mitochondria-associated membranes in alternative mitophagy during the chronic phase of HFD consumption.
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