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Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis.

Mitochondria play central roles in integrating pro- and antiapoptotic stimuli, and JNK is well known to have roles in activating apoptotic pathways. We establish a critical link between stress-induced JNK activation, mitofusin 2, which is an essential component of the mitochondrial outer membrane fusion apparatus, and the ubiquitin-proteasome system (UPS). JNK phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (E3) Huwe1/Mule/ARF-BP1/HectH9/E3Histone/Lasu1 to mitofusin 2, with the BH3 domain of Huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2, leading to mitochondrial fragmentation and enhanced apoptotic cell death. The stability of a nonphosphorylatable mitofusin 2 mutant is unaffected by stress and protective against apoptosis. Conversely, a mitofusin 2 phosphomimic is more rapidly degraded without cellular stress. These findings demonstrate how proximal signaling events can influence both mitochondrial dynamics and apoptosis through phosphorylation-stimulated degradation of the mitochondrial fusion machinery.

Pubmed ID: 22748923

Authors

  • Leboucher GP
  • Tsai YC
  • Yang M
  • Shaw KC
  • Zhou M
  • Veenstra TD
  • Glickman MH
  • Weissman AM

Journal

Molecular cell

Publication Data

August 24, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: N01-CO-12400
  • Agency: NCI NIH HHS, Id: ZIA BC010292-12

Mesh Terms

  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • Cell Line, Tumor
  • GTP Phosphohydrolases
  • Humans
  • MAP Kinase Kinase 4
  • Mitochondria
  • Mitochondrial Proteins
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Proteolysis
  • Stress, Physiological
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination