Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Koch, Johanna R.; Schmid, Franz X.

doi:10.1038/ncomms4041

Cited by 51 publications

(72 citation statements)

References 37 publications

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“…Protein pull-down experiments revealed direct interaction of recombinant AIF with CHCHD4. This direct protein-protein interaction was not affected by point mutations of cysteine residues in CHCHD4 ( Figure 1C) that previously have been implicated in its mitochondrial activity Fraga et al, 2014;Hofmann et al, 2005;Koch and Schmid, 2014).…”

Section: Aif Interacts With Chchd4mentioning

confidence: 63%

“…The biochemical and functional consequences of AIF depletion phenocopied that of CHCHD4 depletion, causing selective defects of respiratory chain complexes I and IV ( Figures 4A-4E). Moreover, the knockdown of AIF or CHCHD4 had similar effects on the abundance of CHCHD4 substrates (Figures S3C-S3E) NDUFA8 (Szklarczyk et al, 2011), COX17, and DDP1 (Hofmann et al, 2005), which were not detectable in the AIF/ CHCHD4 immunoprecipitate ( Figure S3F), presumably because the interaction between CHCHD4 and its substrates is rather transient (Koch and Schmid, 2014;Sideris et al, 2009). Neither AIF nor CHCHD4 affected the abundance of other mitochondrial proteins such as VDAC, PINK, and HSP60 ( Figures S3C and S3D).…”

Section: Aif Is Required For Chchd4 Protein Expressionmentioning

confidence: 92%

“…Human CHCHD4 is a soluble 16-kDa protein that localizes to the mitochondrial IMS (Hofmann et al, 2005), where it participates in mitochondrial import and catalyzes oxidative protein folding in cooperation with the sulfhydryl oxidase GFER/ALR/Erv1p Chacinska et al, 2008;Fischer et al, 2013;Koch and Schmid, 2014). Endogenous AIF and CHCHD4, which both colocalized in mitochondria (Figure S1B), formed a stable complex that persisted even after the treatment of the cells with the translation inhibitor cycloheximide (CHX) (Figure S1C), and coimmunoprecipitated in conditions in which neither respiratory chain subunits nor GFER were detectable in the complex ( Figure 1B; data not shown).…”

Section: Aif Interacts With Chchd4mentioning

confidence: 99%

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Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

et al. 2015

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.

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Section: Aif Interacts With Chchd4mentioning

confidence: 63%

Section: Aif Is Required For Chchd4 Protein Expressionmentioning

confidence: 92%

Section: Aif Interacts With Chchd4mentioning

confidence: 99%

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Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

et al. 2015

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“…Two forms of the fusion protein, i-form and m-form, were detected. The mutant of b 2 -Mia40 core , in which the third cysteine residue was replaced by serine (C3S), was an exception because this protein is likely unable to fold properly (21). No accumulation of the m-form was observed, whereas the i-form of b 2 -Mia40 core -C3S accumulated at levels similar to other b 2 -Mia40 core variants (Fig.…”

Section: Significancementioning

confidence: 94%

Retro-translocation of mitochondrial intermembrane space proteins

Brągoszewski

Wasilewski

Sakowska

et al. 2015

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

102

101

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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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“…Firstly, whereas the IMS is connected to the cytosol via porins, which allow the free diffusion of molecules of up to 5 kDa (including GSH/GSSG, NADPH/ NADP + or hydrogen peroxide), the matrix is strictly separated from the IMS as the transport across the inner membrane is tightly controlled by substrate-specific carriers. Secondly, most cysteine residues of matrix proteins are believed to be reduced in the matrix, while many IMS proteins contain structural disulfide bonds which are introduced by the mitochondrial disulfide relay (also called MIA pathway) (Chacinska et al, 2004;Naoe et al, 2004;Allen et al, 2005;Mesecke et al, 2005;Bihlmaier et al, 2007;Banci et al, 2009;Kawano et al, 2009;Milenkovic et al, 2009;Bien et al, 2010;von der Malsburg et al, 2011;Fischer et al, 2013;Koch and Schmid, 2014).…”

Section: Introduction -Mitochondria Contain Two Distinct Redox Networkmentioning

confidence: 99%

Thiol switches in mitochondria: operation and physiological relevance

Riemer

Schwarzländer

Conrad

et al. 2015

Biological Chemistry

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Mitochondria are a major source of reactive oxygen species (ROS) in the cell, particularly of superoxide and hydrogen peroxide. A number of dedicated enzymes regulate the conversion and consumption of superoxide and hydrogen peroxide in the intermembrane space and the matrix of mitochondria. Nevertheless, hydrogen peroxide can also interact with many other mitochondrial enzymes, particularly those with reactive cysteine residues, modulating their reactivity in accordance with changes in redox conditions. In this review we will describe the general redox systems in mitochondria of animals, fungi and plants and discuss potential target proteins that were proposed to contain regulatory thiol switches.

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Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Cited by 51 publications

References 37 publications

Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

Retro-translocation of mitochondrial intermembrane space proteins

Thiol switches in mitochondria: operation and physiological relevance

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