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Title: Pathomechanistic Characterization of DMT1-mediated manganese cytotoxicity: Implications in neurodegeneration
Authors: TAI YEE KIT
Keywords: manganese, iron depletion, DMT1, ferritin, JNK, autophagy
Issue Date: 11-Jan-2013
Citation: TAI YEE KIT (2013-01-11). Pathomechanistic Characterization of DMT1-mediated manganese cytotoxicity: Implications in neurodegeneration. ScholarBank@NUS Repository.
Abstract: Iron is the most abundant transition metal in the body. This enigmatic metal is crucial for biological functions as iron deficiency and overload can lead to multiple health issues, including iron-related brain disorders. While the transport of iron requires the divalent metal transporter 1 (DMT1), manganese is similarly transported via DMT1. The co-sharing of DMT1 may compromise iron uptake and intracellular homeostasis during manganese toxicity. Unlike iron, we found that manganese accumulates in the cytoplasm of cells overexpressing DMT1 and mediates loss in cell viability via JNK activation. The resistance of cells to low dose iron toxicity is due to the upregulation of ferritin, which is not observed with manganese treatment. Indeed, we clarified that manganese interferes with iron homeostasis by promoting ferritin degradation via autophagy and JNK phosphorylation. JNK phosphorylation is reversed by thioredoxin overexpression, suggesting the involvement of the ASK1-JNK pathway in manganese-mediated iron depletion.
Appears in Collections:Ph.D Theses (Open)

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