Outer Mitochondrial Membrane Protein Degradation by the Proteasome

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Albert Neutzner1,
  2. Richard J. Youle1 and
  3. Mariusz Karbowski1,2

Published Online: 20 MAY 2008

DOI: 10.1002/9780470725207.ch2

Mitochondrial Biology: New Perspectives: Novartis Foundation Symposium 287

Mitochondrial Biology: New Perspectives: Novartis Foundation Symposium 287

How to Cite

Neutzner, A., Youle, R. J. and Karbowski, M. (2007) Outer Mitochondrial Membrane Protein Degradation by the Proteasome, in Mitochondrial Biology: New Perspectives: Novartis Foundation Symposium 287 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470725207.ch2

Author Information

  1. 1

    Biochemistry Section, Surgical Neurology Branch, National Institutes of Health, Bldg 35, Room 2C917, 25 Convent Drive, MSC 370, Bethesda, MD 20892, USA

  2. 2

    Biotechnology Center, University of Maryland Biotechnology Institute, University of Maryland, 725 W. Lombard St, Baltimore, MD 21201, USA

Publication History

  1. Published Online: 20 MAY 2008
  2. Published Print: 5 OCT 2007

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470066577

Online ISBN: 9780470725207

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Keywords:

  • outer mitochondrial membrane proteins;
  • endoplasmic reticulum-associated degradation;
  • membrane spanning domains;
  • Parkinson's disease;
  • protein ubiquitylation and proteasome degradation

Summary

Protein turnover is used for regulatory processes and to eliminate superfluous, denatured or chemically inactivated polypeptides. Mitochondrial proteins may be particularly susceptible to damage induced by reactive oxygen species and several pathways of mitochondrial proteolysis have been illuminated. However, in contrast to matrix and inner mitochondrial membrane protein degradation, little is known about the turnover of integral outer mitochondrial membrane (OMM) proteins or the mechanisms involved. We have found that pheromone treatment of Saccharomyces cerevisiae induces the proteasome-dependent elimination of the OMM spanning protein, Fzo1, from the mitochondria and that Fzo1 is ubiquitylated while still associated with the membrane. These characteristic processing steps are similar to those of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway suggesting the term OMMAD, outer mitochondrial membrane-associated degradation, to describe the process. ERAD is dependent upon ER membrane spanning RING domain E3 ubiquitin ligases suggesting that certain E3 ligases in the OMM may also regulate OMMAD. This led us to clone and characterize all 54 predicted human gene products that contain both RING domains and predicted membrane spanning domains. A surprising number of these localize to mitochondria where some may control OMMAD. Some of these mitochondrial RING domain proteins also regulate mitochondrial morphology, indicating a critical role of ubiquitin signalling in the maintenance of mitochondrial homeostasis.