In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins

Böttinger, Lena; Górnicka, Agnieszka; Czerwik, Tomasz; Brągoszewski, Piotr; Łoniewska-Lwowska, Adrianna; Schulze‐Specking, Agnes; Truscott, Kaye N.; Guiard, Bernard; Milenkovic, Dusanka; Chacińska, Agnieszka

doi:10.1091/mbc.e12-05-0358

Cited by 44 publications

(59 citation statements)

References 41 publications

(81 reference statements)

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“…This process is facilitated by two essential components of the MIA pathway, Mia40 and Erv1 and leads to trapping of IMS precursors within the organelle due to oxidative folding (47)(48)(49). Mechanistic studies have demonstrated that the MIA pathway relies on the coordinated action of its two central players, Mia40 and Erv1, and also on the reducing power of glutathione, to execute disulfide transfer reactions efficiently by minimizing unproductive intermediate stages (50)(51)(52). These features ensure that the MIA system works efficiently despite the fact that the IMS is continuous with the reducing environment of the cytosol (53).…”

Section: Figmentioning

confidence: 99%

Mitochondrial protein homeostasis

2013

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Mitochondria use 800-1,500 proteins to perform their biological functions in the eukaryotic cells. Distinct transport and sorting mechanisms are responsible for the delivery of proteins to the correct location within mitochondria. Mitochondrial proteins undergo processing events and form functional assemblies.Finally, non-functional proteins are cleared to maintain healthy mitochondria. We provide an overview of the processes collectively contributing to the maintenance of mitochondrial protein homeostasis, which is critical for cell physiology and survival.

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Section: Figmentioning

confidence: 99%

Mitochondrial protein homeostasis

2013

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“…Upon protein synthesis in the cytosol, the cysteine residues of IMS proteins remain in a reduced state, owing to the reducing properties of the cytosolic environment (11,12). After entering the TOM channel, precursor proteins are specifically recognized by Mia40 protein, and their cysteine residues are oxidized through the cooperative action of Mia40 and Erv1 proteins (7,(13)(14)(15)(16)(17). Mia40 is a receptor, folding catalyst, and disulfide carrier, and the Erv1 protein serves as a sulfhydryl oxidase.…”

mentioning

confidence: 99%

Retro-translocation of mitochondrial intermembrane space proteins

Brągoszewski

Wasilewski

Sakowska

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The content of mitochondrial proteome is maintained through two highly dynamic processes, the influx of newly synthesized proteins from the cytosol and the protein degradation. Mitochondrial proteins are targeted to the intermembrane space by the mitochondrial intermembrane space assembly pathway that couples their import and oxidative folding. The folding trap was proposed to be a driving mechanism for the mitochondrial accumulation of these proteins. Whether the reverse movement of unfolded proteins to the cytosol occurs across the intact outer membrane is unknown. We found that reduced, conformationally destabilized proteins are released from mitochondria in a size-limited manner. We identified the general import pore protein Tom40 as an escape gate. We propose that the mitochondrial proteome is not only regulated by the import and degradation of proteins but also by their retro-translocation to the external cytosolic location. Thus, protein release is a mechanism that contributes to the mitochondrial proteome surveillance. Because most mitochondrial proteins originate in the cytosol, mitochondria had to develop a protein import system. Given the complex architecture of these organelles, with two membranes and two aqueous compartments, protein import and sorting require the cooperation of several pathways. The main entry gate for precursor proteins is the translocase of the outer mitochondrial membrane (TOM) complex. Upon entering mitochondria, proteins are routed to different sorting machineries (1-5).Reaching the final location is one step in the maturation of mitochondrial proteins that must be accompanied by their proper folding. The mitochondrial intermembrane space assembly (MIA) pathway for intermembrane space (IMS) proteins illustrates the importance of coupling these processes because this pathway links protein import with oxidative folding (6-10). Upon protein synthesis in the cytosol, the cysteine residues of IMS proteins remain in a reduced state, owing to the reducing properties of the cytosolic environment (11,12). After entering the TOM channel, precursor proteins are specifically recognized by Mia40 protein, and their cysteine residues are oxidized through the cooperative action of Mia40 and Erv1 proteins (7,(13)(14)(15)(16)(17). Mia40 is a receptor, folding catalyst, and disulfide carrier, and the Erv1 protein serves as a sulfhydryl oxidase. The oxidative folding is believed to provide a trapping mechanism that prevents the escape of proteins from the IMS back to the cytosol (10, 13, 18). Our initial result raised a possibility that the reverse process can also occur, as we observed the relocation of in vitro imported Tim8 from mitochondria to the incubation buffer (13). Thus, we sought to establish whether and how this process can proceed in the presence of the intact outer membrane (OM). Our study provides, to our knowledge, the first characterization of the mitochondrial protein retro-translocation. The protein retro-translocation serves as a regulatory and quality control mechanism for th...

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“…In a previous study, we showed that Mia40 had a single midpoint potential of Ϫ290 mV, and at different redox potentials, one disulfide bond was reduced (19). However, recent studies suggested that Mia40 exists in intermediate oxidation states in mitochondria (28,29). Based on earlier publications in the literature that supported that only the CPC motif of Mia40 was redox active and could be reduced, we may have misinterpreted Mia40 oxidation in the presence of excess Tim13 in our previous study such that more than two cysteines of Mia40 were reduced by excess Tim13 (19).…”

Section: Resultsmentioning

confidence: 89%

“…Excess Mia40 can oxidize substrates in vitro (18,19,26), and recent studies in vivo support that Mia40 is present in a partially reduced state (28,29). Whereas these studies show that Mia40 is reduced, the specific redox state of Mia40 has not been determined.…”

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confidence: 93%

Mia40 Protein Serves as an Electron Sink in the Mia40-Erv1 Import Pathway

Neal¹,

Dabir

Tienson³

et al. 2015

Journal of Biological Chemistry

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Background: Oxidized substrates such as Tim13 acquire two disulfide bonds simultaneously, but Mia40 has one active redox center that accepts two electrons. Results: Mia40 can acquire up to six electrons when oxidizing substrates. Conclusion: Mia40 has the flexibility to accept several electrons. Significance: Mechanistic properties of the MIA pathway are unique compared with redox pathways in the endoplasmic reticulum and bacterial periplasm.

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In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins

Cited by 44 publications

References 41 publications

Mitochondrial protein homeostasis

Mitochondrial protein homeostasis

Retro-translocation of mitochondrial intermembrane space proteins

Mia40 Protein Serves as an Electron Sink in the Mia40-Erv1 Import Pathway

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