title: Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis.
abstract: 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.
authors: Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors: Guillaume P
authors: GP
authors: Leboucher
authors: Yien Che
authors: YC
authors: Tsai
authors: Mei
authors: M
authors: Yang
authors: Kristin C
authors: KC
authors: Shaw
authors: Ming
authors: M
authors: Zhou
authors: Timothy D
authors: TD
authors: Veenstra
authors: Michael H
authors: MH
authors: Glickman
authors: Allan M
authors: AM
authors: Weissman
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D013312:Stress, Physiological / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D024101:Mitochondrial Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D048670:MAP Kinase Kinase 4; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human