Abstract
The neurodegeneration induced by manganese has been attributed to its ability to undergo redox cycling, and catalysis of reactive oxygen species (ROS) formation, as with other transition metals. However, the characterization of manganese as a pro-oxidant is confounded by increasing evidence that the metal may scavenge superoxide anions and protect cells from oxidative damage. The current study was designed to address conflicting reports pertaining to the oxidative capacity of manganese. We found that the metal has distinctive redox dynamics in which the divalent reduced form, unlike iron, possessed no intrinsic oxidative capacity. The apparent ability of Mn 2+ to promote the formation of ROS within a cortical mitochondrial-synaptosomal fraction was quenched by the depletion of contaminating nanomolar concentrations of trivalent metals. The addition of manganic ions at trace concentrations dose-dependently restored the oxidative capacity attributed to divalent manganese, whereas the presence of the ferric ion retarded the rate of ROS generation. This result was paralleled by the spectrophotometric demonstration that the kinetics of iron oxidation is accelerated by trivalent but not divalent manganese. The markedly different capacities of the lower and higher valence states of manganese to promote free-radical formation in cortical fractions and to modulate the process of iron oxidation may account for earlier contradictory reports of anti- and pro-oxidant properties of manganese.
Highlights
Manganese toxicity, or manganism, can trigger severe psychiatric and extrapyramidal motor dysfunction, which have frequently been attributed to oxidative damage
The site-specificity of the pathology and the selective targeting of dopamine have led to the comparison of manganese-induced neurodegeneration to that of other transition metals, iron and copper (Triggs and Willmore, 1984; Rauhala and Chiueh, 2000; Sengstock et al, 1993), i.e. the toxicity of manganese has been associated with the general propensity of transition metals to produce cytotoxic levels of free-radicals during redox cycling
In spite of claims that manganese is a pro-oxidant, experimental efforts to investigate the role of the metal in oxidative stress have largely ignored the relationship between valence and the capacity to promote reactive oxygen species (ROS) formation
Summary
Manganism, can trigger severe psychiatric and extrapyramidal motor dysfunction, which have frequently been attributed to oxidative damage. The reduction of copper-dependent low-density lipoprotein conjugation (Tsujimoto et al, 1988), and iron-induced phospholipid peroxidation, by Mn2+ has been demonstrated in mammalian cultured cells (Tampo and Yonaha, 1992) These protective effects contradict reports of a pro-oxidant role for manganese in the divalent state. In the presence of a trivalent chelator, the apparent ability of divalent manganese to promote the formation of reactive oxygen species (ROS) disappeared These observations were complemented by the finding that trivalent manganese increased the rate of iron oxidation, whereas Mn2+ did not alter the ratio of ferrous to ferric. This suggests a mechanism by which manganese has the capacity to be either a pro-oxidant or an anti-oxidant, and highlights the significance of valence and ion speciation in manganese-related oxidative events
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