Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity

Recent studies of speciation of manganese (Mn) in brain mitochondria, neuron-like cells, and astrocytes are reviewed. No evidence is found for oxidation of Mn²⁺ complexes to a Mn³⁺ complex. The only evidence for any Mn³⁺ complex is found in a spectrum essentially identical to that of mitochondrial manganese superoxide dismutase (MnSOD). While this does not prove that no Mn³⁺ is produced in these tissues by oxidation of Mn²⁺, it does suggest that formation of an active Mn³⁺ complex by oxidation of Mn²⁺ probably does not play as important a role in Mn toxicity as has been suggested earlier. Since these results suggest that we should look elsewhere for the proximal causes of Mn neurotoxicity, we consider the possibilities that Mn³⁺ may be transported into the cell via transferrin and that Mn²⁺ may inhibit Ca²⁺-activation and control of the rate of ATP production by oxidative phosphorylation.