Mitochondrial bioactivation of cysteine S-conjugates and 4-thiaalkanoates: Implications for mitochondrial dysfunction and mitochondrial diseases

Add time:08/21/2019    Source:sciencedirect.com

The toxicity of most drugs and chemicals is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles, including mitochondria. The toxicity of haloalkene-derived cysteine S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial bioactivation. Toxic cysteine S-conjugates are formed by the glutathione S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione S-conjugates, which are hydrolyzed by γ-glutamyltransferase and dipeptidases. Mitochondrial cysteine conjugate ß-lyase-catalyzed bioactivation of cysteine S-conjugates affords unstable α-halothiolates. Haloalkene-derived 4-thiaalkanoates, which are analogs of cysteine S-conjugates that lack an α-amino group, undergo bioactivation by the enzymes of fatty acid ß-oxidation to give 3-hydroxy-4-thiaalkanoates that eliminate α-halothiolates. α-Halothiolates yield alkylating and acylating agents that interact with cellular macromolecules and thereby cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine nucleotide concentrations, depletion of the mitochondrial glutathione content, perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are seen with cysteine S-conjugates. Similar changes are observed with cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and hypoglycemia are also observed.

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