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Iron mitigates DMT1-mediated manganese cytotoxicity via the ASK1-JNK signaling axis: Implications of iron supplementation for manganese toxicity

Y. Tai,K. C. Chew,B. W. Tan,K. Lim,T. Soong

Published 2016 in Scientific Reports

ABSTRACT

Manganese (Mn2+) neurotoxicity from occupational exposure is well documented to result in a Parkinson-like syndrome. Although the understanding of Mn2+ cytotoxicity is still incomplete, both Mn2+ and Fe2+ can be transported via the divalent metal transporter 1 (DMT1), suggesting that competitive uptake might disrupt Fe2+ homeostasis. Here, we found that DMT1 overexpression significantly enhanced Mn2+ cytoplasmic accumulation and JNK phosphorylation, leading to a reduction in cell viability. Although a robust activation of autophagy was observed alongside these changes, it did not trigger autophagic cell death, but was instead shown to be essential for the degradation of ferritin, which normally sequesters labile Fe2+. Inhibition of ferritin degradation through the neutralization of lysosomal pH resulted in increased ferritin and enhanced cytoplasmic Fe2+ depletion. Similarly, direct Fe2+ chelation also resulted in aggravated Mn2+-mediated JNK phosphorylation, while Fe2+ repletion protected cells and this occurs via the ASK1-thioredoxin pathway. Taken together, our study presents the novel findings that Mn2+ cytotoxicity involves the depletion of the cytoplasmic Fe2+ pool and the increase in autophagy-lysosome activity is important to maintain Fe2+ homeostasis. Thus, Fe2+ supplementation could have potential applications in the prevention and treatment of Mn2+-mediated toxicity.

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