title: Effect of mitochondrial complex I inhibition on Fe-S cluster protein activity.
abstract: Iron-sulfur (Fe-S) clusters are small inorganic cofactors formed by tetrahedral coordination of iron atoms with sulfur groups. Present in numerous proteins, these clusters are involved in key biological processes such as electron transfer, metabolic and regulatory processes, DNA synthesis and repair and protein structure stabilization. Fe-S clusters are synthesized mainly in the mitochondrion, where they are directly incorporated into mitochondrial Fe-S cluster-containing proteins or exported for cytoplasmic and nuclear cluster-protein assembly. In this study, we tested the hypothesis that inhibition of mitochondrial complex I by rotenone decreases Fe-S cluster synthesis and cluster content and activity of Fe-S cluster-containing enzymes. Inhibition of complex I resulted in decreased activity of three Fe-S cluster-containing enzymes: mitochondrial and cytosolic aconitases and xanthine oxidase. In addition, the Fe-S cluster content of glutamine phosphoribosyl pyrophosphate amidotransferase and mitochondrial aconitase was dramatically decreased. The reduction in cytosolic aconitase activity was associated with an increase in iron regulatory protein (IRP) mRNA binding activity and with an increase in the cytoplasmic labile iron pool. Since IRP activity post-transcriptionally regulates the expression of iron import proteins, Fe-S cluster inhibition may result in a false iron deficiency signal. Given that inhibition of complex I and iron accumulation are hallmarks of idiopathic Parkinson's disease, the findings reported here may have relevance for understanding the pathophysiology of this disease.
authors.affiliation: Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Santiago, Chile.
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Mena
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Bulteau
authors.forename: Julio
authors.initials: J
authors.lastname: Salazar
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Marco T
authors.initials: MT
authors.lastname: Núñez
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000201:enzymology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D006801:Humans; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D012402:Rotenone / Q000494:pharmacology
chemical_list: D007506:Iron-Sulfur Proteins; D012402:Rotenone; C546175:ACO1 protein, human; D000154:Aconitate Hydratase; D035941:Iron Regulatory Protein 1; D042967:Electron Transport Complex I