Mia40 Combines Thiol Oxidase and Disulfide Isomerase Activity to Efficiently Catalyze Oxidative Folding in Mitochondria

Koch, Johanna R.; Schmid, Franz X.

doi:10.1016/j.jmb.2014.10.022

Cited by 19 publications

(25 citation statements)

References 44 publications

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“…There has been considerable discussion regarding the need for a protein disulfide isomerase activity in the context of oxidative protein folding within the IMS [16, 31, 32, 35]. While a number of IMS client proteins have simple patterns of disulfide connectivity, and might therefore not require a dedicated isomerase, others proteins show more complicated folds and contain multiple disulfide bonds.…”

Section: Resultsmentioning

confidence: 99%

“…While a number of IMS client proteins have simple patterns of disulfide connectivity, and might therefore not require a dedicated isomerase, others proteins show more complicated folds and contain multiple disulfide bonds. In an interesting prior study, Koch and Schmid [35] followed the oxidative refolding of 5 µM rRNase in the presence of 2 µM Mia40 and a glutathione redox buffer (3 mM GSH/ 0.3 mM GSSG). The regain of enzymatic activity observed over corresponding controls (amounting to ~25% over 5 h) was very modest considering that the substrate RNase was only present at a 2.5-fold higher concentration over Mia40.…”

Section: Resultsmentioning

confidence: 99%

“…However Mia40 has been shown to be a poor isomerase towards scrambled Cox17 in the presence of the same redox buffer used in Figure 5 [35]. The Cox17 construct employed for those experiments contained two structural disulfides and no free cysteine residues.…”

Section: Resultsmentioning

confidence: 99%

“…The increase in absorbance A 296 – A 310 reflects the hydrolysis of cCMP. Subtraction of the absorbance at 310 nm improved the signal to noise ratio as described previously [35]. Relative activities of the aliquots were determined by comparing the slope of the initial rates with those of an equivalent concentration of native RNase.…”

Section: Methodsmentioning

confidence: 99%

“…DRE2, ATP23, Erv1/lfALR, Ccs1, SOD1, and anamorsin contain neither the classical cysteine motifs nor ITS import sequences, although they have been shown to be Mia40 clients in vivo and/or in vitro [15, 31–34]. Schmid and coworkers further probed the substrate specificity of Mia40 by using cysteine mutants of IMS proteins [35, 36]. They demonstrated that rather than a precisely defined sequence, regions of hydrophobicity adjacent to cysteine residues are sufficient for binding and covalent capture by Mia40 [36].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Hudson

Thorpe

2015

Archives of Biochemistry and Biophysics

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Mia40 participates in oxidative protein folding within the mitochondrial intermembrane space (IMS) by mediating the transfer of reducing equivalents from client proteins to FAD-linked oxidoreductases of the Erv1 family (lfALR in mammals). Here we investigate the specificity of the human Mia40/lfALR system towards non-cognate unfolded protein substrates to assess whether the efficient introduction of disulfides requires a particular amino acid sequence context or the presence of an IMS targeting signal. Reduced pancreatic ribonuclease A (rRNase), avian lysozyme, and riboflavin binding protein are all competent substrates of the Mia40/lfALR system, although they lack those sequence features previously thought to direct disulfide bond formation in cognate IMS substrates. The oxidation of rRNase by Mia40 does not limit overall turnover of unfolded substrate by the Mia40/lfALR system. Mia40 is an ineffective protein disulfide isomerase when its ability to restore enzymatic activity from scrambled RNase is compared to that of protein disulfide isomerase. Mia40’s ability to bind amphipathic peptides is evident by avid binding to the isolated B-chain during the insulin reductase assay. In aggregate these data suggest that the Mia40/lfALR system has a broad sequence specificity and that potential substrates may be protected from adventitious oxidation by kinetic sequestration within the mitochondrial IMS.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Hudson

Thorpe

2015

Archives of Biochemistry and Biophysics

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Maintenance of small molecule redox homeostasis in mitochondria

Jacobs

Riemer

2022

FEBS Letters

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Compartmentalisation of eukaryotic cells enables fundamental otherwise often incompatible cellular processes. Establishment and maintenance of distinct compartments in the cell relies not only on proteins, lipids and metabolites but also on small redox molecules. In particular, small redox molecules such as glutathione, NAD(P)H and hydrogen peroxide (H 2 O 2 ) cooperate with protein partners in dedicated machineries to establish specific subcellular redox compartments with conditions that enable oxidative protein folding and redox signalling. Dysregulated redox homeostasis has been directly linked with a number of diseases including cancer, neurological disorders, cardiovascular diseases, obesity, metabolic diseases and ageing. In this review, we will summarise mechanisms regulating establishment and maintenance of redox homeostasis in the mitochondrial subcompartments of mammalian cells.

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Oxidative protein folding in the intermembrane space of human mitochondria

Zarges,

Riemer

2024

FEBS Open Bio

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The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.

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Mia40 Combines Thiol Oxidase and Disulfide Isomerase Activity to Efficiently Catalyze Oxidative Folding in Mitochondria

Cited by 19 publications

References 44 publications

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Maintenance of small molecule redox homeostasis in mitochondria

Oxidative protein folding in the intermembrane space of human mitochondria

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