title: Nε-(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells.
abstract: Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic β-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGE-damaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with well-organized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSA-induced mitophage formation. Our study demonstrated that CML-BSA induced mitochondrial dysfunction and mitophagy in pancreatic β-cells. The findings from this study suggest that increased concentration of AGEs may damage β-cells and reduce insulin secretion.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medical Laboratory Sciences and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;
authors.forename: Mei-Chen
authors.identifier: http://orcid.org/0000-0001-9432-9066
authors.initials: MC
authors.lastname: Lo
authors.affiliation: Department of Pathology, Saint Paul's Hospital, Tao-Yuan, Taiwan;
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
authors.affiliation: School of Medical Laboratory Sciences and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;
authors.forename: Chin-I
authors.initials: CI
authors.lastname: Lu
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; and.
authors.forename: Chuang-Rung
authors.initials: CR
authors.lastname: Chang
authors.affiliation: School of Medical Laboratory Sciences and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medical Laboratory Sciences and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Institute of Pharmaceutical Sciences and Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan leehorng@tmu.edu.tw.
authors.forename: Horng-Mo
authors.initials: HM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D019587:Dietary Supplements; D015536:Down-Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008239:Lysine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D063154:Mitochondrial Dynamics / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000819:agonists / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008063:Thioctic Acid / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C000593873:Ager protein, mouse; D000975:Antioxidants; D015415:Biomarkers; D017127:Glycation End Products, Advanced; D007328:Insulin; D016877:Oxidants; D000067759:Receptor for Advanced Glycation End Products; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; C048496:N(6)-carboxymethyllysine; D008063:Thioctic Acid; D008239:Lysine
keywords: advanced glycated end products; diabetes; mitochondrial dynamics; mitophagy