Mia40 is a Trans-site Receptor That Drives Protein Import into the Mitochondrial Intermembrane Space by Hydrophobic Substrate Binding

Overview

Journal Elife

Specialty Biology

Date 2016 Jun 26

PMID 27343349

Citations 39

Authors

Valentina Peleh

Emmanuelle Cordat

Johannes M Herrmann

Affiliations

Soon will be listed here.

Abstract

Many proteins of the mitochondrial IMS contain conserved cysteines that are oxidized to disulfide bonds during their import. The conserved IMS protein Mia40 is essential for the oxidation and import of these proteins. Mia40 consists of two functional elements: an N-terminal cysteine-proline-cysteine motif conferring substrate oxidation, and a C-terminal hydrophobic pocket for substrate binding. In this study, we generated yeast mutants to dissect both Mia40 activities genetically and biochemically. Thereby we show that the substrate-binding domain of Mia40 is both necessary and sufficient to promote protein import, indicating that trapping by Mia40 drives protein translocation. An oxidase-deficient Mia40 mutant is inviable, but can be partially rescued by the addition of the chemical oxidant diamide. Our results indicate that Mia40 predominantly serves as a trans-site receptor of mitochondria that binds incoming proteins via hydrophobic interactions thereby mediating protein translocation across the outer membrane by a 'holding trap' rather than a 'folding trap' mechanism.

Citing Articles

MIA40 suppresses cell death induced by apoptosis-inducing factor 1.

Mussulini B, Maruszczak K, Draczkowski P, Borrero-Landazabal M, Ayyamperumal S, Wnorowski A EMBO Rep. 2025; .

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Interaction with the cysteine-free protein HAX1 expands the substrate specificity and function of MIA40 beyond protein oxidation.

Rothemann R, Stobbe D, Hoehne-Wiechmann M, Murschall L, Peker E, Knaup L FEBS J. 2024; 291(24):5506-5522.

PMID: 39564806 PMC: 11653687. DOI: 10.1111/febs.17328.

Oxidative protein folding in the intermembrane space of human mitochondria.

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Oxidation of COX19 Using the Combined Action of ERV1 and Glutathione.

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Mitochondrial Dynamics during Development.

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References

Matlack K, Misselwitz B, Plath K, Rapoport T . BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell. 1999; 97(5):553-64. DOI: 10.1016/s0092-8674(00)80767-9. View

Esaki M, Kanamori T, Nishikawa S, Endo T . Two distinct mechanisms drive protein translocation across the mitochondrial outer membrane in the late step of the cytochrome b(2) import pathway. Proc Natl Acad Sci U S A. 1999; 96(21):11770-5. PMC: 18361. DOI: 10.1073/pnas.96.21.11770. View

Jan P, Esser K, Pratje E, Michaelis G . Som1, a third component of the yeast mitochondrial inner membrane peptidase complex that contains Imp1 and Imp2. Mol Gen Genet. 2000; 263(3):483-91. DOI: 10.1007/s004380051192. View

Lee J, Hofhaus G, Lisowsky T . Erv1p from Saccharomyces cerevisiae is a FAD-linked sulfhydryl oxidase. FEBS Lett. 2000; 477(1-2):62-6. DOI: 10.1016/s0014-5793(00)01767-1. View

Luciano P, Vial S, Vergnolle M, Dyall S, Robinson D, Tokatlidis K . Functional reconstitution of the import of the yeast ADP/ATP carrier mediated by the TIM10 complex. EMBO J. 2001; 20(15):4099-106. PMC: 149141. DOI: 10.1093/emboj/20.15.4099. View

Diekert K, de Kroon A, Ahting U, Niggemeyer B, Neupert W, de Kruijff B . Apocytochrome c requires the TOM complex for translocation across the mitochondrial outer membrane. EMBO J. 2001; 20(20):5626-35. PMC: 125676. DOI: 10.1093/emboj/20.20.5626. View

Curran S, Leuenberger D, Oppliger W, Koehler C . The Tim9p-Tim10p complex binds to the transmembrane domains of the ADP/ATP carrier. EMBO J. 2002; 21(5):942-53. PMC: 125908. DOI: 10.1093/emboj/21.5.942. View

Vial S, Lu H, Allen S, Savory P, Thornton D, Sheehan J . Assembly of Tim9 and Tim10 into a functional chaperone. J Biol Chem. 2002; 277(39):36100-8. DOI: 10.1074/jbc.M202310200. View

Curran S, Leuenberger D, Schmidt E, Koehler C . The role of the Tim8p-Tim13p complex in a conserved import pathway for mitochondrial polytopic inner membrane proteins. J Cell Biol. 2002; 158(6):1017-27. PMC: 2173223. DOI: 10.1083/jcb.200205124. View

10.

Kadokura H, Katzen F, Beckwith J . Protein disulfide bond formation in prokaryotes. Annu Rev Biochem. 2003; 72:111-35. DOI: 10.1146/annurev.biochem.72.121801.161459. View

11.

Wiedemann N, Kozjak V, Prinz T, Ryan M, Meisinger C, Pfanner N . Biogenesis of yeast mitochondrial cytochrome c: a unique relationship to the TOM machinery. J Mol Biol. 2003; 327(2):465-74. DOI: 10.1016/s0022-2836(03)00118-9. View

12.

Lutz T, Neupert W, Herrmann J . Import of small Tim proteins into the mitochondrial intermembrane space. EMBO J. 2003; 22(17):4400-8. PMC: 202364. DOI: 10.1093/emboj/cdg421. View

13.

GLICK B, Brandt A, Cunningham K, Muller S, Hallberg R, Schatz G . Cytochromes c1 and b2 are sorted to the intermembrane space of yeast mitochondria by a stop-transfer mechanism. Cell. 1992; 69(5):809-22. DOI: 10.1016/0092-8674(92)90292-k. View

14.

Koehler C . The small Tim proteins and the twin Cx3C motif. Trends Biochem Sci. 2004; 29(1):1-4. DOI: 10.1016/j.tibs.2003.11.003. View

15.

Herlan M, Bornhovd C, Hell K, Neupert W, Reichert A . Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J Cell Biol. 2004; 165(2):167-73. PMC: 2172034. DOI: 10.1083/jcb.200403022. View

16.

Curran S, Leuenberger D, Leverich E, Hwang D, Beverly K, Koehler C . The role of Hot13p and redox chemistry in the mitochondrial TIM22 import pathway. J Biol Chem. 2004; 279(42):43744-51. DOI: 10.1074/jbc.M404878200. View

17.

Chacinska A, Pfannschmidt S, Wiedemann N, Kozjak V, Sanjuan Szklarz L, Schulze-Specking A . Essential role of Mia40 in import and assembly of mitochondrial intermembrane space proteins. EMBO J. 2004; 23(19):3735-46. PMC: 522791. DOI: 10.1038/sj.emboj.7600389. View

18.

Naoe M, Ohwa Y, Ishikawa D, Ohshima C, Nishikawa S, Yamamoto H . Identification of Tim40 that mediates protein sorting to the mitochondrial intermembrane space. J Biol Chem. 2004; 279(46):47815-21. DOI: 10.1074/jbc.M410272200. View

19.

Mesecke N, Terziyska N, Kozany C, Baumann F, Neupert W, Hell K . A disulfide relay system in the intermembrane space of mitochondria that mediates protein import. Cell. 2005; 121(7):1059-69. DOI: 10.1016/j.cell.2005.04.011. View

20.

Allen S, Balabanidou V, Sideris D, Lisowsky T, Tokatlidis K . Erv1 mediates the Mia40-dependent protein import pathway and provides a functional link to the respiratory chain by shuttling electrons to cytochrome c. J Mol Biol. 2005; 353(5):937-44. DOI: 10.1016/j.jmb.2005.08.049. View