A mitophagic response to iron overload-induced oxidative damage associated with the PINK1/Parkin pathway in pancreatic beta cells |
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| Institution: | 1. Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA;2. Charlie Norwood VA Medical Center, Augusta, GA, USA;3. Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA;4. Vascular Biology Center, Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA;5. Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA;1. King’s College London, Department of Nutritional Sciences, School of Life Course Sciences, Metal Metabolism Group, London, UK;2. Kings College London, Centre for Developmental Neurobiology, London, UK;1. Univ Lyon, Univ Jean Monnet, INSERM, U 1059 SainBioSE, F-42023 Saint-Etienne, France;2. University Hospital Saint-Etienne, Department of Gynecology and Obstetrics, F-42055 Saint-Etienne, France;3. Mines Saint-Etienne, Univ Lyon, Univ Jean Monnet, INSERM, U 1059 Sainbiose, Centre CIS, F-42023 Saint-Etienne, France;1. Professor of Medicine and Epidemiology & Community Medicine, University of Ottawa Senior Scientist, Ottawa Hospital Research Institute Scientist, Institute for Clinical Evaluative Sciences, Ottawa, Canada;2. Department of Medicine, University of Ottawa, Ottawa, Canada;3. Department of Pathology & Lab. Medicine, University of Ottawa Clinical Biochemist - Division of Biochemistry, The Ottawa Hospital, Ottawa, Canada |
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| Abstract: | BackgroundIron overload can result in a disorder in glucose metabolism. However, the underlining mechanism through which iron overload induces beta cell death remains unknown.MethodsAccording to the concentration of ferric ammonium citrate (FAC) and N-acetylcysteine, INS-1 cells were randomly divided into four groups: normal control (FAC 0 μM) group, FAC 80 μM group, FAC 160 μM group, FAC 160μM + NAC group. Cell proliferation was assessed by Cell Counting Kit-8. Reactive oxygen species (ROS) level was further evaluated using flow cytometer with a fluorescent probe. The mitochondrial membrane potential was detected by JC-1 kit, and transmission electron microscopy was used to observe the mitochondrial changes. The related protein expressions were detected by western bolt to evaluate mitophagy status.ResultsIt was shown that FAC treatment decreased INS-1 cell viability in vitro, resulted in a decline in mitochondrial membrane potential, increased oxidative stress level and suppressed mitophagy. Furthermore, these effects could be alleviated by the ROS scavenger.ConclusionsWe proved that increased iron overload primarily increased oxidative stress and further suppressed mitophagy via PTEN-induced putative kinase 1/Parkin pathway, resulting in cytotoxicity in INS-1 cells. |
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| Keywords: | Iron overload Pancreatic beta cell ROS Mitophagy |
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