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J Cell Physiol. 2018 Sep;233(9):7080-7091. doi: 10.1002/jcp.26346. Epub 2018 Mar 25.

Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria.

Author information

1
Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
2
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
3
Chinese Medicine Department, China Medical University Beigang Hospital, Taichung, Taiwan.
4
School of Chinese Medicine, China Medical University, Taichung, Taiwan.
5
Cancer Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.
6
Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.
7
Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan.
8
Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan.
9
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
10
Department of Sports Sciences, University of Taipei, Taipei, Taiwan.
11
Department of Healthcare Administration, Asia University, Taichung, Taiwan.
12
Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taichung.

Abstract

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.

KEYWORDS:

IGF-IIR; Rab9; heart failure; mitophagy

PMID:
29574782
DOI:
10.1002/jcp.26346

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