title: Upregulation of mitochondrial ferritin by proinflammatory cytokines: implications for a role in Alzheimer's disease.
abstract: Studies have shown an increased expression of mitochondrial ferritin (FtMt) and an antioxidant role for the protein in the brains of Alzheimer's disease (AD) patients. However, little information is available concerning the role of FtMt in other AD pathologies, including inflammation and amyloidogenesis. Therefore, we investigated the regulation and function of FtMt in inflammation and amyloidogenesis. FtMt protein expression was increased by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), whereas FtMt mRNA levels were increased by TNF-α but not by IL-1β or IL-6 in IMR-32 cells. The transcription factor nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, suppressed this TNF-α-induced FtMt expression. FtMt overexpression increased NF-κB activity and translocation of p65 into the nucleus in HEK293 cells. Conversely, knockdown of FtMt attenuated TNF-α-induced NF-κB activity. Overexpression of FtMt inhibited TNF-α-induced apoptosis in the cell culture. FtMt overexpression reduced iron-mediated expression of amyloid-β protein precursor and decreased NF-κB-dependent increases in β- and γ-secretase, leading to decreased amyloid-β production. Our data provide new insights into the mechanism underlying the regulation of FtMt expression by proinflammatory cytokines and indicate further roles for FtMt in AD.
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Mingchun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
authors.forename: Shigeko
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Yanagisawa
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Psychiatry, Faculty of Medicine, The University of British Columbia, Vancouver BC, Canada.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Vincent
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tooyama
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010088:Oxidoreductases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016229:Amyloid beta-Peptides; D016207:Cytokines; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D009570:Nitriles; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013450:Sulfones; D051996:Transcription Factor RelA; C556634:mitochondrial ferritin, human; D005293:Ferritins; D003513:Cycloheximide; C454461:FTH1 protein, human; D010088:Oxidoreductases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; NF-κB; amyloid-β; inflammation; iron; mitochondrial ferritin