The disulfide relay system of mitochondria is connected to the respiratory chain

Bihlmaier, Karl; Mesecke, Nikola; Terziyska, Nadia; Bien, Melanie; Hell, Kai; Herrmann, Johannes M.

doi:10.1083/jcb.200707123

Cited by 192 publications

(179 citation statements)

References 31 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…The resultant reduced form of Mia40 is oxidized by a sulfhydryl oxidase Erv1 in the IMS for the next round of disulfide bond transfer (7,8). Reduced Erv1 is oxidized by cytochrome c, which is then oxidized by electron transfer to either the cytochrome oxidase complex or to cytochrome c peroxidase (12,13). The disulfide transfer reaction mediated by Mia40 is promoted by another small protein in the IMS, Hot13 (9).…”

Section: Structural Basis Of Yeast Tim40/mia40 As An Oxidative Translmentioning

confidence: 99%

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Kawano

Yamano²,

Naoé³

et al. 2009

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

View full text Add to dashboard Cite

The mitochondrial intermembrane space (IMS) contains many small cysteine-bearing proteins, and their passage across the outer membrane and subsequent folding require recognition and disulfide bond transfer by an oxidative translocator Tim40/Mia40 in the inner membrane facing the IMS. Here we determined the crystal structure of the core domain of yeast Mia40 (Mia40C4) as a fusion protein with maltose-binding protein at a resolution of 3 Å. The overall structure of Mia40C4 is a fruit-dish-like shape with a hydrophobic concave region, which accommodates a linker segment of the fusion protein in a helical conformation, likely mimicking a bound substrate. Replacement of the hydrophobic residues in this region resulted in growth defects and impaired assembly of a substrate protein. The Cys296-Cys298 disulfide bond is close to the hydrophobic concave region or possible substrate-binding site, so that it can mediate disulfide bond transfer to substrate proteins. These results are consistent with the growth phenotypes of Mia40 mutant cells containing Ser replacement of the conserved cysteine residues.

show abstract

Section: Structural Basis Of Yeast Tim40/mia40 As An Oxidative Translmentioning

confidence: 99%

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Kawano

Yamano²,

Naoé³

et al. 2009

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

View full text Add to dashboard Cite

show abstract

“…Finally, the FAD-reduced Erv1 (Erv1-FADH 2 ) is re-oxidized by transferring the electrons to either oxidized cytochrome c (cyt c) or molecular oxygen, thereby regenerating Erv1 activity. Through the Erv1 interaction with cyt c, the MIA pathway is linked to the respiratory chain [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

Ceh-Pavia

Ang

Spiller

et al. 2014

Biochemical Journal

View full text Add to dashboard Cite

Erv1 (essential for respiration and viability 1) is an FADdependent thiol oxidase of the Erv/ALR (augmenter of liver regeneration) sub-family. It is an essential component of the mitochondrial import and assembly (MIA) pathway, playing an important role in the oxidative folding of the mitochondrial intermembrane space (IMS) proteins and linking the MIA pathway to the mitochondrial respiratory chain via cytochrome c (cyt c). The importance of the Erv/ALR enzymes was also demonstrated in a recent study where a single mutation in the human ALR (R194H) leads to autosomal recessive myopathy [Di Fonzo, Ronchi, Lodi, Fassone, Tigano, Lamperti, Corti, Bordoni, Fortunato, Nizzardo et al. (2009) Am. J. Hum. Genet. 84, 594-604]. However, the molecular mechanism of the disease is still unclear. In the present study, we use yeast Erv1 as a model to provide clear evidence for a progressive functional defect in the catalytic activity of the corresponding Erv1 R182H mutant. We show that the FAD cofactor was released from Erv1 R182H during its catalytic cycle, which led to the inactivation of the enzyme. We also characterized the effects of the mutation on the folding and stability of Erv1 and tested our in vitro findings in vivo using a yeast genetic approach. The results of the present study allow us to provide a model for the functional defect in Erv1 R182H, which could potentially be extended to human ALR R194H and provides insights into the molecular basis of autosomal recessive myopathy.

show abstract

“…Reduced Mia40 is reoxidized by Erv1, which results in the activation of Mia40 for the next round of precursor binding and import Grumbt et al, 2007). Additional components contribute in the execution of the MIA pathway, including cytochrome c and cytochrome c peroxidase, which play a role in electron flow from Erv1, and the zinc-binding Hot13 that promotes the reoxidation of Mia40 by Erv1 (Curran et al, 2004;Bihlmaier et al, 2007;Dabir et al, 2007;Mesecke et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…On completion of disulfide exchange, precursor monomers are released in an oxidized state capable of assembly into mature complexes (Curran et al, 2002;Lu et al, 2004;Webb et al, 2006;Müller et al, 2008 Erv1, which results in the activation of Mia40 for the next round of precursor binding and import Grumbt et al, 2007). Additional components contribute in the execution of the MIA pathway, including cytochrome c and cytochrome c peroxidase, which play a role in electron flow from Erv1, and the zinc-binding Hot13 that promotes the reoxidation of Mia40 by Erv1 (Curran et al, 2004;Bihlmaier et al, 2007;Dabir et al, 2007;Mesecke et al, 2008). Mia40 is able to distinguish its own substrates from other cysteine-rich, but otherwise unrelated, proteins in the formation of disulfide-bonded intermediates (Milenkovic et al, 2007a).…”

mentioning

confidence: 99%

Identification of the Signal Directing Tim9 and Tim10 into the Intermembrane Space of Mitochondria

Milenkovic

Ramming

Müller

et al. 2009

MBoC

150

140

View full text Add to dashboard Cite

The intermembrane space of mitochondria contains the specific mitochondrial intermembrane space assembly (MIA) machinery that operates in the biogenesis pathway of precursor proteins destined to this compartment. The Mia40 component of the MIA pathway functions as a receptor and binds incoming precursors, forming an essential early intermediate in the biogenesis of intermembrane space proteins. The elements that are crucial for the association of the intermembrane space precursors with Mia40 have not been determined. In this study, we found that a region within the Tim9 and Tim10 precursors, consisting of only nine amino acid residues, functions as a signal for the engagement of substrate proteins with the Mia40 receptor. Furthermore, the signal contains sufficient information to facilitate the transfer of proteins across the outer membrane to the intermembrane space. Thus, here we have identified the mitochondrial intermembrane space sorting signal required for delivery of proteins to the mitochondrial intermembrane space. INTRODUCTIONMitochondria pose a great challenge for the proper delivery of proteins because of their complex architecture. Mitochondrial precursors must find their way to one of the four mitochondrial subcompartments: the outer membrane, intermembrane space, inner membrane, or matrix. As a direct consequence of this complexity, several machineries for the translocation and sorting of mitochondrial precursors have evolved. Interplay between these machineries and specific signals present in the precursors drive different protein targeting pathways (Schatz and Dobberstein, 1996;Emanuelsson and von Heijne, 2001;Jensen and Johnson, 2001;Endo et al., 2003;Koehler, 2004;Oka and Mihara, 2005;Dolezal et al., 2006;Neupert and Herrmann, 2007;Bolender et al., 2008). Initially, mitochondrial precursors are recognized in a signal-dependent manner by specific receptors and are transferred across the barrier of outer mitochondrial membrane by using the translocase of the outer membrane (TOM) complex. On the trans-side of the outer mitochondrial membrane, sorting machineries decode specific signals in precursors, and this results in the branching of protein import pathways. The most well characterized is the presequence pathway across the inner membrane driven by a cleavable and positively charged signal sequence, called a presequence, and the translocase of the inner membrane (TIM) 23 complex Endo et al., 2003;Oka and Mihara, 2005;Neupert and Herrmann, 2007;Bolender et al., 2008). The presequence is cleaved off by a specific protease liberating the mature protein. However, other mitochondrial signals are not proteolytically removed and remain as part of the native mitochondrial protein. One example is the recently identified ␤-signal that is recognized by the sorting and assembly machinery (SAM) complex to sort ␤-barrel proteins to the mitochondrial outer membrane . In other mitochondrial membrane proteins, the membrane domains, anchors, and their surrounding regions are used to some extent for selection of ...

show abstract

The disulfide relay system of mitochondria is connected to the respiratory chain

Cited by 192 publications

References 31 publications

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

Identification of the Signal Directing Tim9 and Tim10 into the Intermembrane Space of Mitochondria

Contact Info

Product

Resources

About