Figure 7

A proposed model of cellular Mn²⁺ toxicity via DMT1.

(a) Under normal conditions, cells acquire adequate amounts of Fe²⁺ through cellular uptake via DMT1 and degradation of ferritin to maintain the labile iron pool (LIP). (b) However, Mn²⁺ overexposure competes with Fe²⁺ for uptake by DMT1. In addition, the accumulation Mn²⁺ in the cytoplasm disrupts LIP, resulting in enhanced autophagy to degrade ferritin for Fe²⁺ mobilization. Mn²⁺-mediated cellular iron depletion also results in the activation of JNK via the TRX-ASK1 pathway, leading to cell death.