title: Human mitochondrial thioredoxin reductase reduces cytochrome c and confers resistance to complex III inhibition.
abstract: The ubiquitously expressed mammalian thioredoxin reductases are selenoproteins that together with NADPH regenerate active reduced thioredoxins and are involved in diverse actions mediated by redox control. Two main forms of mammalian thioredoxin reductases have been isolated, one cytosolic (TrxR1) and one present in mitochondria (TrxR2). Although the principal target for TrxRs is thioredoxin, the cytosolic form can regenerate several important antioxidants such as ascorbic acid, lipoic acid, and ubiquinone. In this study we demonstrate that cytochrome c is a substrate for both TrxR1 and TrxR2. In addition, cells overexpressing TrxR2 are more resistant to impairment of complex III in the mitochondrial respiratory chain upon both antimycin A and myxothiazol treatments, suggesting a complex III bypassing function of TrxR2. Furthermore, we show that cytochrome c is reduced by TrxR2 in vitro, not only by using NADPH as an electron donor but also by using NADH, pointing at TrxR2 as an important redox protein on complex III impairment. These findings may be valuable in understanding respiratory disorders in mitochondrial diseases.
authors.affiliation: Department of Biosciences at Novum, Center for Biotechnology, Karolinska Institutet, SE-141 57 Huddinge, Sweden.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nalvarte
authors.forename: Anastasios E
authors.initials: AE
authors.lastname: Damdimopoulos
authors.forename: Giannis
authors.initials: G
authors.lastname: Spyrou
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008689:Methacrylates; D008928:Mitochondria / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D017279:Selenocysteine / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D008689:Methacrylates; D013844:Thiazoles; D017279:Selenocysteine; D009243:NAD; D013879:Thioredoxins; D009249:NADP; D000968:Antimycin A; C030517:myxothiazol; D045304:Cytochromes c; C516124:TXNRD1 protein, human; C516127:TXNRD2 protein, human; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase; D014450:Electron Transport Complex III