title: Redox control of human mitochondrial outer membrane protein MitoNEET [2Fe-2S] clusters by biological thiols and hydrogen peroxide.
abstract: The human mitochondrial outer membrane protein mitoNEET is a novel target of the type II diabetes drug pioglitazone. The C-terminal cytosolic domain of mitoNEET hosts a redox-active [2Fe-2S] cluster via an unusual ligand arrangement of three cysteine residues and one histidine residue. Here we report that human mitoNEET [2Fe-2S] clusters are fully reduced when expressed in Escherichia coli cells. In vitro studies show that purified mitoNEET [2Fe-2S] clusters can be partially reduced by monothiols such as reduced glutathione, L-cysteine or N-acetyl-L-cysteine and fully reduced by dithiothreitol or the E. coli thioredoxin/thioredoxin reductase system under anaerobic conditions. Importantly, thiol-reduced mitoNEET [2Fe-2S] clusters can be reversibly oxidized by hydrogen peroxide without disruption of the clusters in vitro and in E. coli cells, indicating that mitoNEET may act as a sensor of oxidative signals to regulate mitochondrial functions via its [2Fe-2S] clusters. Furthermore, the binding of the type II diabetes drug pioglitazone in mitoNEET effectively inhibits the thiol-mediated reduction of [2Fe-2S] clusters, suggesting that pioglitazone may modulate the function of mitoNEET by blocking the thiol-mediated reduction of [2Fe-2S] clusters in the protein.
authors.affiliation: From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Landry
authors.forename: Huangen
authors.initials: H
authors.lastname: Ding
mesh_terms: D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D007506:Iron-Sulfur Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D000077205:Pioglitazone; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C525595:CISD1 protein, human; D007004:Hypoglycemic Agents; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D016877:Oxidants; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D006861:Hydrogen Peroxide; D000077205:Pioglitazone
keywords: Diabetes; Hydrogen Peroxide; Iron-Sulfur Protein; Redox Regulation; Thioredoxin