Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria
Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria
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DOI：
10.1002/jcp.26346
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发表时间：
2018-09-01
影响因子：
5.6
通讯作者：
Huang, Chih-Yang
中科院分区：
文献类型：
--
作者：
Huang, Chih-Yang;Kuo, Wei-Wen;Huang, Chih-Yang
线粒体功能障碍是线粒体吞噬的主要特征，在线粒体质量控制中起着至关重要的作用。然而，在许多疾病中，过度的有丝分裂导致细胞死亡，包括缺血性中风和肝毒性。胰岛素样生长因子II(IGF-II)及其受体(IGF-IIR)在高血压心力衰竭的发生发展中起重要作用。我们发现IGF-II触发IGF-IIR受体激活，导致线粒体功能障碍，导致有丝分裂和心肌细胞死亡。这些结果表明，IGF-IIR激活触发了线粒体的碎裂，导致自噬小体的形成和线粒体内容物的丢失。这些结果与依赖于Parkin的有丝分裂吞噬有关。此外，自噬蛋白ATG5和ATG7缺乏并不能抑制IGF-IIR诱导的有丝分裂吞噬。然而，Rab9基因敲除减少了线粒体的吞噬作用，并维持了线粒体的功能。这些结构性有丝分裂噬菌体通过IGF-IIR激活，引发线粒体丢失和线粒体ROS积聚，从而导致心肌细胞存活率下降。综上所述，我们的结果表明，IGF-IIR主要通过依赖Rab9的替代自噬诱导有丝分裂吞噬。
Mitochondria dysfunction is the major characteristic of mitophagy, which is essential in mitochondrial quality control. However, excessive mitophagy contributes to cell death in a number of diseases, including ischemic stroke and hepatotoxicity. Insulin-like growth factor II (IGF-II) and its receptor (IGF-IIR) play vital roles in the development of heart failure during hypertension. We found that IGF-II triggers IGF-IIR receptor activation, causing mitochondria dysfunction, resulting in mitophagy, and cardiomyocyte cell death. These results indicated that IGF-IIR activation triggers mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. These results are associated with Parkin-dependent mitophagy. Additionally, autophagic proteins Atg5, and Atg7 deficiency did not suppress IGF-IIR-induced mitophagy. However, Rab9 knockdown reduced mitophagy and maintained mitochondrial function. These constitutive mitophagies through IGF-IIR activation trigger mitochondria loss and mitochondrial ROS accumulation for cardiomyocyte viability decrease. Together, our results indicate that IGF-IIR predominantly induces mitophagy through the Rab9-dependent alternative autophagy.