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Machinery for protein sorting and assembly in the mitochondrial outer membrane

Abstract

Mitochondria contain translocases for the transport of precursor proteins across their outer and inner membranes1,2,3,4,5. It has been assumed that the translocases also mediate the sorting of proteins to their submitochondrial destination1,2,5,6,7,8,9,10. Here we show that the mitochondrial outer membrane contains a separate sorting and assembly machinery (SAM) that operates after the translocase of the outer membrane (TOM). Mas37 forms a constituent of the SAM complex. The central role of the SAM complex in the sorting and assembly pathway of outer membrane proteins explains the various pleiotropic functions that have been ascribed to Mas37 (refs 4, 11–15). These results suggest that the TOM complex, which can transport all kinds of mitochondrial precursor proteins, is not sufficient for the correct integration of outer membrane proteins with a complicated topology, and instead transfers precursor proteins to the SAM complex.

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Figure 1: Mas37-deficient mitochondria are defective in biogenesis of Tom40, but not inner membrane or matrix proteins.
Figure 2: Mas37 is required for assembly of outer membrane proteins.
Figure 3: The SAM complex.
Figure 4: Tom40 precursor is transported to the SAM complex by means of the TOM complex.

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References

  1. Koehler, C. M., Merchant, S. & Schatz, G. How membrane proteins travel across the mitochondrial intermembrane space. Trends Biochem. Sci. 24, 428–432 (1999)

    Article  CAS  Google Scholar 

  2. Herrmann, J. M. & Neupert, W. Protein transport into mitochondria. Curr. Opin. Microbiol. 3, 210–214 (2000)

    Article  CAS  Google Scholar 

  3. Jensen, R. E. & Johnson, A. E. Opening the door to mitochondrial protein import. Nature Struct. Biol. 8, 1008–1010 (2001)

    Article  CAS  Google Scholar 

  4. Endo, T. & Kohda, D. Functions of outer membrane receptors in mitochondrial protein import. Biochim. Biophys. Acta 1592, 3–14 (2002)

    Article  CAS  Google Scholar 

  5. Pfanner, N. & Geissler, A. Versatility of the mitochondrial protein import machinery. Nature Rev. Mol. Cell. Biol. 2, 339–349 (2001)

    Article  CAS  Google Scholar 

  6. Rapaport, D. & Neupert, W. Biogenesis of Tom40, core component of the TOM complex of mitochondria. J. Cell Biol. 146, 321–331 (1999)

    Article  CAS  Google Scholar 

  7. Model, K. et al. Multistep assembly of the protein import channel of the mitochondrial outer membrane. Nature Struct. Biol. 8, 361–370 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Krimmer, T. et al. Biogenesis of porin of the outer mitochondrial membrane involves an import pathway via receptors and the general import pore of the TOM complex. J. Cell Biol. 152, 289–300 (2001)

    Article  CAS  Google Scholar 

  9. Taylor, R. D., McHale, B. J. & Nargang, F. E. Characterization of Neurospora crassa Tom40 deficient mutants and effect of specific mutations on Tom40 assembly. J. Biol. Chem. 278, 765–775 (2003)

    Article  CAS  Google Scholar 

  10. Rapaport, D. Biogenesis of the mitochondrial TOM complex. Trends Biochem. Sci. 27, 191–197 (2002)

    Article  CAS  Google Scholar 

  11. Gratzer, S. et al. Mas37p, a novel receptor subunit for protein import into mitochondria. J. Cell Biol. 129, 25–34 (1995)

    Article  CAS  Google Scholar 

  12. Hachiya, N. et al. Reconstitution of the initial steps of mitochondrial protein import. Nature 376, 705–709 (1995)

    Article  ADS  CAS  Google Scholar 

  13. Ryan, M. T., Müller, H. & Pfanner, N. Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane. J. Biol. Chem. 274, 20619–20627 (1999)

    Article  CAS  Google Scholar 

  14. Abdul, K. M. et al. Functional analysis of human metaxin in mitochondrial protein import in cultured cells and its relationship with the Tom complex. Biochem. Biophys. Res. Commun. 276, 1028–1034 (2000)

    Article  CAS  Google Scholar 

  15. Lithgow, T., Junne, T., Suda, K., Gratzer, S. & Schatz, G. The mitochondrial outer membrane protein Mas22p is essential for protein import and viability of yeast. Proc. Natl Acad. Sci. USA 91, 11973–11977 (1994)

    Article  ADS  CAS  Google Scholar 

  16. Dekker, P. J. T. et al. The Tim core complex defines the number of mitochondrial translocation contact sites and can hold arrested preproteins in the absence of matrix Hsp70-Tim44. EMBO J. 16, 5408–5419 (1997)

    Article  CAS  Google Scholar 

  17. Dietmeier, K. et al. Tom5 functionally links mitochondrial preprotein receptors to the general import pore. Nature 388, 195–200 (1997)

    Article  ADS  CAS  Google Scholar 

  18. Sogo, L. F. & Yaffe, M. P. Regulation of mitochondrial morphology and inheritance by Mdm10p, a protein of the mitochondrial outer membrane. J. Cell Biol. 126, 1361–1373 (1994)

    Article  CAS  Google Scholar 

  19. Martelli, P. L., Fariselli, P., Krogh, A. & Casadio, R. A sequence-profile-based HMM for predicting and discriminating β barrel membrane proteins. Bioinformatics 18 (Suppl. 1), S46–S53 (2002)

    Article  Google Scholar 

  20. Sesaki, H. & Jensen, R. E. UGO1 encodes an outer membrane protein required for mitochondrial fusion. J. Cell Biol. 152, 1123–1134 (2001)

    Article  CAS  Google Scholar 

  21. van Wilpe, S. et al. Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase. Nature 401, 485–489 (1999)

    Article  ADS  CAS  Google Scholar 

  22. Meisinger, C. et al. Protein import channel of the outer mitochondrial membrane: a highly stable Tom40-Tom22 core structure differentially interacts with preproteins, small Tom proteins, and import receptors. Mol. Cell. Biol. 21, 2337–2348 (2001)

    Article  CAS  Google Scholar 

  23. Matouschek, A. & Glick, B. S. Barreling through the outer membrane. Nature Struct. Biol. 8, 284–286 (2001)

    Article  CAS  Google Scholar 

  24. Hill, K. et al. Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins. Nature 395, 516–521 (1998)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank M. G. Douglas, C. K. Kassenbrock, D. Cyr and A. Strub for yeast mutants, and R. Casadio for secondary structure prediction. This work was supported by the Deutsche Forschungsgemeinschaft (C.M.), Sonderforschungsbereich 388, Max Planck Research Award/Alexander von Humboldt Foundation/BMBF, the Fonds der Chemie/BMBF (N.P.) and a long-term FEBS fellowship (A.C.).

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Correspondence to Nils Wiedemann.

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Wiedemann, N., Kozjak, V., Chacinska, A. et al. Machinery for protein sorting and assembly in the mitochondrial outer membrane. Nature 424, 565–571 (2003). https://doi.org/10.1038/nature01753

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