Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA
Proposed mechanism for the toxicity of organomercury. (a) As a lipophilic cation, ethylmercury will become concentrated inside astrocytes, following the plasma membrane potential of 45 mV , by a factor of 5.6 fold, and cytosolic ethlymercury will partition into the mitochondria by a factor of 1,000 fold, its accumulation driven by the approximate 180 mV mitochondrial membrane potential . (b) Inside the mitochondria ethylmercury will react and cap thiols/selenols, including the cysteine residues of iron-sulfur centers. The formation of ethylmercuricthiol adducts will not only cause enzyme inhibition, but also increase the levels of free iron inside the mitochondria. (c) The release of iron catalyzes Fenton/Haber-Weiss chemistry leading to the formation of the highly oxidizing HO•. HO• has multiple targets, including sensors of the permeability transition complex and also mtDNA. High levels of HO• cause Mitoposis, leading to cytochrome c release from the mitochondria and the initiation of apoptosis.
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