title: Iron overload-induced calcium signals modulate mitochondrial fragmentation in HT-22 hippocampal neuron cells.
abstract: Iron is necessary for neuronal functions; however, excessive iron accumulation caused by impairment of iron balance could damage neurons. Neuronal iron accumulation has been observed in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nevertheless, the precise mechanisms underlying iron toxicity in neuron cells are not fully understood. In this study, we investigated the mechanism underlying iron overload-induced mitochondrial fragmentation in HT-22 hippocampal neuron cells that were incubated with ferric ammonium citrate (FAC). Mitochondrial fragmentation via dephosphorylation of Drp1 (Ser637) and increased apoptotic neuronal death were observed in FAC-stimulated HT-22 cells. Furthermore, the levels of intracellular calcium (Ca(2+)) were increased by iron overload. Notably, chelation of intracellular Ca(2+) rescued mitochondrial fragmentation and neuronal cell death. In addition, iron overload activated calcineurin through the Ca(2+)/calmodulin and Ca(2+)/calpain pathways. Pretreatment with the calmodulin inhibitor W13 and the calpain inhibitor ALLN attenuated iron overload-induced mitochondrial fragmentation and neuronal cell death. Therefore, these findings suggest that Ca(2+)-mediated calcineurin signals are a key player in iron-induced neurotoxicity by regulating mitochondrial dynamics. We believe that our results may contribute to the development of novel therapies for iron toxicity related neurodegenerative disorders.
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Dong Gil
authors.initials: DG
authors.lastname: Lee
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Junghyung
authors.initials: J
authors.lastname: Park
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.affiliation: National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheonbuk-do, Republic of Korea.
authors.forename: Sang-Rae
authors.initials: SR
authors.lastname: Lee
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. Electronic address: lee1@knu.ac.kr.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry; D006624:Hippocampus / Q000166:cytology; D007501:Iron / Q000633:toxicity; D019190:Iron Overload / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D005290:Ferric Compounds; D007976:Leupeptins; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C063261:acetylleucyl-leucyl-norleucinal; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide; D007501:Iron; D019703:Calcineurin; D002154:Calpain; C486391:Dnm1l protein, mouse; D034281:Dynamins; D002118:Calcium; C013531:ferric ammonium citrate
keywords: Calcineurin; Calcium; Iron overload; Mitochondrial dynamics; Neurotoxicity