Mitochondrial quality control by the ubiquitin-proteasome system.

Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondria-associated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle 42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights into the interaction of the UPS (ubiquitin-proteasome system) with the OMM. In yeast, Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97 to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy. Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the maintenance of cellular and therefore organismal viability.

[1]  J. Duncan.  Mitochondrial dysfunction in diabetic cardiomyopathy. , 2011, Biochimica et biophysica acta.

[2]  N. Mizushima,et al.  Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane*♦ , 2011, The Journal of Biological Chemistry.

[3]  Sonja Hess,et al.  Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy , 2011, Human molecular genetics.

[4]  S. Fang,et al.  The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover , 2011, Molecular biology of the cell.

[5]  M. Glickman,et al.  Ubiquitin-proteasome system and mitochondria - reciprocity. , 2011, Biochimica et biophysica acta.

[6]  R. Youle,et al.  Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin , 2010, The Journal of cell biology.

[7]  J. Brodsky,et al.  A Cdc48p-associated Factor Modulates Endoplasmic Reticulum-associated Degradation, Cell Stress, and Ubiquitinated Protein Homeostasis* , 2010, The Journal of Biological Chemistry.

[8]  G. Shadel,et al.  Stressed-out mitochondria get MAD. , 2010, Cell metabolism.

[9]  R. Youle,et al.  Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL , 2010, The Journal of cell biology.

[10]  S. Gygi,et al.  A stress-responsive system for mitochondrial protein degradation. , 2010, Molecular cell.

[11]  I. Mata,et al.  The Genetics of Parkinson Disease , 2010, Journal of geriatric psychiatry and neurology.

[12]  R. Youle,et al.  Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells , 2010, Proceedings of the National Academy of Sciences.

[13]  M. Brand,et al.  Rapid turnover of mitochondrial uncoupling protein 3. , 2010, The Biochemical journal.

[14]  M. Brand,et al.  Degradation of an intramitochondrial protein by the cytosolic proteasome , 2010, Journal of Cell Science.

[15]  S. Dimauro,et al.  Metabolic Myopathies , 2010, Current rheumatology reports.

[16]  R. Youle,et al.  Mechanisms of mitophagy , 2010, Nature Reviews Molecular Cell Biology.

[17]  T. Langer,et al.  AAA proteases in mitochondria: diverse functions of membrane-bound proteolytic machines. , 2009, Research in microbiology.

[18]  S. Yanagi,et al.  Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation. , 2009, Molecular biology of the cell.

[19]  T. Tatsuta.  Protein quality control in mitochondria. , 2009, Journal of biochemistry.

[20]  R. Youle,et al.  Role of the Ubiquitin Conjugation System in the Maintenance of Mitochondrial Homeostasis , 2008, Annals of the New York Academy of Sciences.

[21]  D. Germain.  Ubiquitin‐dependent and ‐independent mitochondrial protein quality controls: implications in ageing and neurodegenerative diseases , 2008, Molecular microbiology.

[22]  R. Youle,et al.  Parkin is recruited selectively to impaired mitochondria and promotes their autophagy , 2008, The Journal of cell biology.

[23]  J. Hayashi,et al.  ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis , 2008, Science.

[24]  David M. Hockenbery,et al.  Hsp90 Inhibition Decreases Mitochondrial Protein Turnover , 2007, PloS one.

[25]  Zee-Yong Park,et al.  A proteomics approach to identify the ubiquitinated proteins in mouse heart. , 2007, Biochemical and biophysical research communications.

[26]  K. Sada,et al.  A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics , 2006, The EMBO journal.

[27]  Marty C. Brandon,et al.  Mitochondrial mutations in cancer , 2006, Oncogene.

[28]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[29]  B. Westermann,et al.  Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast. , 2003, Molecular biology of the cell.

[30]  Tom A. Rapoport,et al.  The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol , 2001, Nature.

[31]  S. Melov,et al.  Mitochondrial disease in mouse results in increased oxidative stress. , 1999, Proceedings of the National Academy of Sciences of the United States of America.