Upregulation of Mitochondrial Ferritin by Proinflammatory Cytokines: Implications for a Role in Alzheimer's Disease

Article type: Research Article

Authors: Yang, Hongkuan^{a; b} | Guan, Hongpeng^{a; b} | Yang, Mingchun^{a; b} | Liu, Ziyi^{a; b} | Takeuchi, Shigeko^a | Yanagisawa, Daijiro^a | Vincent, Steven R.^{a; c} | Zhao, Shiguang^{b; *} | Tooyama, Ikuo^{a; *}

Affiliations: [a] Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan | [b] Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China | [c] Department of Psychiatry, Faculty of Medicine, The University of British Columbia, Vancouver BC, Canada

Correspondence: [*] Correspondence to: Ikuo Tooyama, MD, PhD, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan. Tel.: +81 77 548 2330; Fax: +81 77 548 2402; E-mail: [email protected] and Shiguang Zhao, MD, PhD, Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150001, China. Tel.: +86 451 53629254; Fax: +86 451 53629254; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β, inflammation, iron, mitochondrial ferritin, NF-κB

DOI: 10.3233/JAD-142595

Journal: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 797-811, 2015