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

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-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin 6 (IL-6), whereas FtMt mRNA levels were increased by TNF-alpha but not by IL-1 beta or IL-6 in IMR-32 cells. The transcription factor nuclear factor-kappa B (NF-kappa B) inhibitor, Bay 11-7082, suppressed this TNF-alpha-induced FtMt expression. FtMt overexpression increased NF-kappa B activity and translocation of p65 into the nucleus in HEK293 cells. Conversely, knockdown of FtMt attenuated TNF-alpha-induced NF-kappa B activity. Overexpression of FtMt inhibited TNF-alpha-induced apoptosis in the cell culture. FtMt overexpression reduced iron-mediated expression of amyloid-beta protein precursor and decreased NF-kappa B-dependent increases in beta- and gamma-secretase, leading to decreased amyloid-beta 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.