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 Mn(2+) complexes to a Mn(3+) complex. The only evidence for any Mn(3+) complex is found in a spectrum essentially identical to that of mitochondrial manganese superoxide dismutase (MnSOD). While this does not prove that no Mn(3+) is produced in these tissues by oxidation of Mn(2+), it does suggest that formation of an active Mn(3+) complex by oxidation of Mn(2+) 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 Mn(3+) may be transported into the cell via transferrin and that Mn(2+) may inhibit Ca(2+)-activation and control of the rate of ATP production by oxidative phosphorylation.