Manganese toxicity primarily causes loss of dopamine in the striatum and devastation of the cells of the globus pallidus (GP) associated with the symptoms of rigidity and dystonia. It has often been hypothesized that loss of dopamine (DA) is through oxidation induced by Mn3+ and there is evidence that Mn3+ can oxidize Da, But there is very limited evidence on the amount of Mn3+ present in mitochondria and cells. While oxidation by Mn3+ may explain loss of DA, it does not satisfactory explain the cell loss particularly in the GP. We hypothesize that this cell loss may be mitochondrially linked. Past work has shown that Mn2+ traverses the mitochondrial inner membrane via the mitochondrial Ca2+ transport mechanisms. Ca2+ increases Mn2+ uptake via the uniporter and intramitochondrial Mn2 inhibits Ca2+ efflux via both the Na+dependent and Na+- independent efflux mechanisms. In the presence of physiological amounts of Mg2+ in the external medium, Mn2 can even increase Ca2 influx via the uniporter by displacing Mg2+ from the uniporter activation site. These Mn2+ effects increase the amount of Ca2+ present within the mitochondrial matrix. Genrally, increasing matrix Ca2+ has been found to increase the probability of inducing the mitochondrial permeability transition (MPT), and opening of the MPT leads to mitochondrial swelling, which can cause tearing of the outer membrane, loss of cytochrome c from the intermembrane space and apoptosis. Mn is not transported via the very active Na+- dependent efflux mechanism but only by the very slow Na+- independent mechanism in brain explaining its retention in brain mitochondria. We propose; 1) to study Mn speciation in mitochondria and cells using the shift in position of the Mn absorption edge with oxidation state to distinguish and quantify the oxidation states of Mn. This latter approach is called X-ray near edge structure (XANES) spectroscopy. 2) to evaluate the hypothesis of mitochondrially-linked cell killing by Mn, outlined above, and 3) to investigate Mn2+ effects on a recently discovered mechanism of mitochondrial Ca2+ uptake, the RaM, which could play an important role in control of cellular metabolism.

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National Institute of Environmental Health Sciences (NIEHS)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Kirshner, Annette G
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University of Rochester
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Gunter, Thomas E; Gerstner, Brent; Gunter, Karlene K et al. (2013) Manganese transport via the transferrin mechanism. Neurotoxicology 34:118-27
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