title: ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells.
abstract: Mitochondrial dysfunction induces apoptosis of pancreatic β-cells and leads to type 2 diabetes, but the mechanism involved in this process remains unclear. Chronic endoplasmic reticulum (ER) stress plays a role in the apoptosis of pancreatic β-cells; therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced β-cells apoptosis. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse pancreatic β-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2α, GRP78 and GRP 94, as well as ER stress-associated apoptotic factor, CHOP, and activated JNK. AMP-activated protein kinase (AMPK) was also activated under mitochondria dysfunction by metabolic stress. However, the inhibition of AMPK by treatment with compound C, inhibitor of AMPK, and overexpression of mutant dominant negative AMPK (AMPKK45R) blocked the induction of ER stress, which was consist-ent with the decreased β-cell apoptosis and increase of insulin content. Furthermore, mitochondrial dysfunction increased the expression of the inducible nitric oxide synthase (iNOS) gene and the production of nitric oxide (NO), but NO production was prevented by compound C and mutant dominant negative AMPK (AMPK-K45R). Moreover, treatment with 1400W, which is an inhibitor of iNOS, prevented ER stress and apoptosis induced by mitochondrial dysfunction. Treatment of MIN6N8 cells with lipid mixture, physiological conditions of impaired mitochondria function, activated AMPK, increased NO production and induced ER stress. Collectively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic β-cells apoptosis.
authors.affiliation: School of Korean Medicine, Pusan National University, Yangsan 609-735, Korea.
authors.forename: June Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Yeo
authors.forename: Myeong Ho
authors.initials: MH
authors.lastname: Jung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin; D008562:Membrane Glycoproteins; D009840:Oligomycins; C053387:endoplasmin; C032456:antimycin; D051742:Transcription Factor CHOP; D009569:Nitric Oxide; D000968:Antimycin A; D019001:Nitric Oxide Synthase; D055372:AMP-Activated Protein Kinases; D048670:MAP Kinase Kinase 4