title: Miro1-mediated mitochondrial dysfunction under high nutrient stress is linked to NOD-like receptor 3 (NLRP3)-dependent inflammatory responses in rat pancreatic beta cells.
abstract: Type 2 Diabetes (T2D) is associated with a state of low-grade inflammation that leads to insulin resistance under sustained high-fat and glucose (HFG) stress. Mitochondria from pancreatic beta cells play an essential role by metabolizing nutrients and generating signals required for both triggering and amplifying pathways of insulin secretion responding to HFG. However, the underlying pathway linking mitochondrial function to initiate and integrate inflammatory responses within the pancreatic beta cells under HFG stress remains poorly defined. Here, we demonstrated that HFG induced Ca(2+)-mediated deleterious effects on mitochondrial rho GTPase 1 (Miro1), a protein allowing mitochondria to move along microtubules to regulate mitochondria dynamics. This redistribution of Miro1 by HFG led to aggravation of proinflammatory responses in rat islets due to damaged mitochondria-producing reactive oxygen species (ROS). In addition, HFG-induced Ca(2+)-mediated increased expression of mitochondrial dynamin-like protein (DLP1) was assembled on the outer membrane of mitochondria to initiate fission events. Higher expression of DLP1 induced mitochondria fragmentation as expected but was not essential for ROS-induced proinflammatory responses, while Miro1-mediated mitochondrial dysfunction induced proinflammatory responses under HFG stress. Combined, we proposed in this study that HFG stress caused mtROS release mainly through Miro1-mediated effects on mitochondria in pancreatic beta cells triggering the NLRP3-dependent proinflammatory responses and, subsequently, damaged insulin secretion.
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Gao
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China; College of Basic Medical Sciences, Central Laboratory of the Fourth Affiliated Hospital in Xiangyang, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Sang
authors.affiliation: Animal Experiment Center, General Hospital of Guangzhou Military Command, Guangzhou, 510010, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Zhongnan Hospital, Wuhan University 430071, People's Republic of China.
authors.forename: Tian
authors.initials: T
authors.lastname: Zheng
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Pan
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Dai
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: ABSL-3 Laboratory at the Center for Animal Experiment and State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan 430071, People's Republic of China. Electronic address: 00030941@whu.edu.cn.
authors.forename: Sijun
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007340:Insulinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C540072:Rhot1 protein, rat; D020741:rho GTP-Binding Proteins; D002118:Calcium
keywords: Calcium; DLP1; High nutrient; Miro1; Proinflammatory responses