Abstract
Rise in plasma free fatty acids (FFAs) represents a major risk factor for obesity-induced type 2 diabetes. Saturated FFAs cause a progressive decline in insulin secretion by promoting pancreatic β-cell death through increased production of reactive oxygen species (ROS). Recent studies have demonstrated that palmitate (a C16-FFA)-induced rise in ROS causes β-cell death by triggering mitochondrial fragmentation, but the underlying mechanisms are unclear. Using the INS1-832/13 β-cell line, here we demonstrate that palmitate generates the ROS required for mitochondrial fission by activating NOX (NADPH oxidase)-2. More importantly, we show that chemical inhibition, RNAi-mediated silencing and knockout of ROS-sensitive TRPM (transient receptor potential melastatin)-2 channels prevent palmitate-induced mitochondrial fission. Although TRPM2 activation affects the intracellular dynamics of Ca2+ and Zn2+, chelation of Zn2+ alone was sufficient to prevent mitochondrial fission. Consistent with the role of Zn2+, palmitate caused a rise in mitochondrial Zn2+, leading to Zn2+-dependent mitochondrial recruitment of Drp-1 (a protein that catalyses mitochondrial fission) and loss of mitochondrial membrane potential. In agreement with the previous reports, Ca2+ caused Drp-1 recruitment, but it failed to induce mitochondrial fission in the absence of Zn2+. These results indicate a novel role for Zn2+ in mitochondrial dynamics. Inhibition or knockout of TRPM2 channels in mouse islets and RNAi-mediated silencing of TRPM2 expression in human islets prevented FFA/cytokine-induced β-cell death, findings that are consistent with the role of abnormal mitochondrial fission in cell death. To conclude, our results reveal a novel, potentially druggable signalling pathway for FFA-induced β-cell death. The cascade involves NOX-2-dependent production of ROS, activation of TRPM2 channels, rise in mitochondrial Zn2+, Drp-1 recruitment and abnormal mitochondrial fission.
Highlights
Rise in plasma free fatty acids (FFAs) represents a major risk factor for obesity-induced type 2 diabetes
We have examined the effect of palmitate (500 μM, as a complex bovine serum albumin) and high glucose (HG: 20 mM) on mitochondrial dynamics of the rat pancreatic INS-1 832/13 β-cell line
We investigated the mechanism by which palmitate induces abnormal mitochondrial fission.[12]
Summary
Rise in plasma free fatty acids (FFAs) represents a major risk factor for obesity-induced type 2 diabetes. A key cellular target of glucolipotoxicity is mitochondria.[7,9,10,11] Studies have shown that exposure of β-cells to palmitate, one of the most abundant FFAs in the plasma, leads to extensive breakdown of healthy mitochondrial network to small, dysfunctional fragments, leading to mitochondrial dysfunction and β-cell death.[12] in muscle cells, palmitate enhances mitochondrial fission, leading to their loss of insulin sensitivity.[13] Consistent with these in vitro studies, β-cells from diabetes-prone obese Zucker rats show a 25% reduction in mitochondrial network,[14] whereas C57BL/6 mice fed with high-fat diet (HFD) display fragmented mitochondria in their muscle.[13] pharmacological inhibition of mitochondrial breakdown prevents HFD-induced T2D in mice.[13] More importantly, patients with T2D and obesity show reduced mitochondrial size compared with lean subjects.[15,16,17] multiple lines of evidence indicate a relationship between mitochondrial dynamics and obesityassociated T2D. Mitochondrial fission is catalysed by the dynamin-related protein, (Drp)-1, which constricts mitochondria at sites where specific adaptors (Mff, Mid[49,50,51] and Fis1) are located.[18,22]
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