1. Miro1-mediated mitochondrial dysfunction under high nutrient stress is linked to NOD-like receptor 3 (NLRP3)-dependent inflammatory responses in rat pancreatic beta cells.
- Author
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Gao, Jianfeng, Sang, Ming, Zhang, Xiaoyu, Zheng, Tian, Pan, Jiawen, Dai, Ming, Zhou, Li, and Yang, Sijun
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MITOCHONDRIAL pathology , *PANCREATIC beta cells , *INFLAMMATION , *TYPE 2 diabetes , *HIGH-fat diet , *LABORATORY rats - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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