Research Papers: Pathology:
Inhibition of Miro1 disturbs mitophagy and pancreatic β-cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes
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Lingling Chen1,2,*, Chunyan Liu1,*, Jianfeng Gao1, Zhiwen Xie3, Lawrence W.C. Chan4, Damien J. Keating5, Yibin Yang6 , Jiazhong Sun7 , Fuling Zhou8, Yongchang Wei9, Xiuli Men10 and Sijun Yang1
1 ABSL-3 Laboratory at the Center for Animal Experiment and Institute of Animal Model for Human Disease, Wuhan University School of Medicine, Wuhan, P. R. China
2 Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, P.R. China
3 School of Bioscience and Technology , Weifang Medical University, Weifang Shandong, P.R. China
4 Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong
5 Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
6 Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
7 Department of Respiratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
8 Department of Hematology and Radiation, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
9 Department of Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
10 School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, P.R. China
* These authors have contributed equally to this work
Sijun Yang, email:
Keywords: Miro1, mitophagy, insulin resistance, HFD, diabetes, Pathology Section
Received: June 26, 2017 Accepted: August 29, 2017 Published: September 16, 2017
Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified. Here we show firstly that the expression of Miro is reduced in human T2D and mouse db/db islets and in INS-1 cell line exposed to high glucose and palmitate. β-cell specific ablation of Miro1 (Miro1f/f: Rip-cre mice, or (IKO) under high nutrient stress promotes the development of hyperglycemia. β-cells from IKO mice display an inhibition of mitophagy under oxidative stress and induces mitochondrial dysfunction. Dysfunctional mitophagy in IKO mice is represented by damaged islet beta cell mitochondrial and secretory capacity, unbalanced downstream MKK-JNK signalling without affecting the levels of MEK, ERK or p38 activation and subsequently, impaired insulin secretion signaling via inhibition IRS-AKT-Foxo1 pathway, leading to worsening glucose tolerance in these mice. Thus, these data suggest that Miro1 may be responsible for mitophagy deficiency and β-cell dysfunction in T2D and that strategies target Miro1 in vivo may provide a therapeutic target to enhance β-cell mitochondrial quality and insulin secretion to ameliorate complications associated with T2D.
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