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

摘要

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.