Thiol-disulphide redox regulation has a key role during the biogenesis of mitochondrial intermembrane space (IMS) proteins. Only the Cys-reduced form of precursor proteins can be imported into mitochondria, which is followed by disulphide bond formation in the mitochondrial IMS. In contrast to the wealth of knowledge on the oxidation process inside mitochondria, little is known about how precursors are maintained in an importcompetent form in the cytosol. Here we provide the first evidence that the cytosolic thioredoxin system is required to maintain the IMS small Tim proteins in reduced forms and facilitate their mitochondrial import during respiratory growth.Keywords: redox regulation; mitochondrial import; thioredoxin; oxidoreductase; folding EMBO reports (2012) 13, 916-922.
Thiol-disulphide redox regulation has a key role during the biogenesis of mitochondrial intermembrane space (IMS) proteins. Only the Cys-reduced form of precursor proteins can be imported into mitochondria, which is followed by disulphide bond formation in the mitochondrial IMS. In contrast to the wealth of knowledge on the oxidation process inside mitochondria, little is known about how precursors are maintained in an importcompetent form in the cytosol. Here we provide the first evidence that the cytosolic thioredoxin system is required to maintain the IMS small Tim proteins in reduced forms and facilitate their mitochondrial import during respiratory growth.Keywords: redox regulation; mitochondrial import; thioredoxin; oxidoreductase; folding EMBO reports (2012) 13, 916-922.
Erv1, a member of the FAD-dependent Erv1/ALR disulphide bond generating enzyme family, is a key player of the MIA pathway. Although considerable progress has been made, the molecular mechanism of electron transfer within Erv1 is still not fully understood. The reduction potentials of the three redox centres were previously determined to be À320 mV for the shuttle disulphide, À150 mV for the active-site disulphide and À215 mV for FAD cofactor. However, it is unknown why FAD of Erv1 has such a low potential compared with other sulfhydryl oxidases, and why the shuttle disulphide has a potential as low as many of the stable structural disulphides of the substrates of MIA pathway. In this study, the three reduction potentials of Erv1 were reassessed using the wild-type and inactive mutants of Erv1 under anaerobic conditions. Our results show that the standard potentials for the shuttle and active-site disulphides are approximately À250 mV and À215~À260 mV, respectively, and the potential for FAD cofactor is À148 mV. Our results support a model that both disulphide bonds are redox-active, and electron flow in Erv1 is thermodynamically favourable. Furthermore, the redox behaviour of Erv1 was confirmed, for the first time using Mia40, the physiological electron donor of Erv1. Together with previous studies on proteins of MIA pathway, we conclude that electron flow in the MIA pathway is a thermodynamically favourable, smoothly downhill process for all steps. Database Erv1: EC 1.8.3.2.Abbreviations ALR, augmenter of liver regeneration; DTT, dithiothreitol; Erv, essential for respiration and viability; FAD, flavin adenine dinucleotide; IMS, intermembrane space; MIA, mitochondrial import and assembly; QSOX, quiescin sulfhydryl oxidase; TCEP, tris(2-carboxyethyl)phosphine.Electron flow mechanism of MIA40 pathway E. Ceh-Pavia et al.
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