Stress-Induced Phosphorylation and Proteasomal Degradation of Mitofusin 2 Facilitates Mitochondrial Fragmentation and Apoptosis

• Published in: Molecular cell 2012-08, Vol.47 (4), p.547-557
• Main Authors: Leboucher, Guillaume P., Tsai, Yien Che, Yang, Mei, Shaw, Kristin C., Zhou, Ming, Veenstra, Timothy D., Glickman, Michael H., Weissman, Allan M.
• Format: Article
• Language: English
• Subjects: apoptosis; Apoptosis - physiology; BH3 Interacting Domain Death Agonist Protein - metabolism; Cell Line, Tumor; GTP Phosphohydrolases - metabolism; Humans; MAP Kinase Kinase 4 - metabolism; membrane fusion; mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; mitochondrial membrane; Mitochondrial Proteins - metabolism; mitogen-activated protein kinase; mutants; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Stress, Physiological - physiology; Tumor Suppressor Proteins; Ubiquitin - metabolism; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.05.041

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. [Display omitted] ► Mitofusin 2 is degraded by the ubiquitin-proteasome system in response to stress ► Mitofusin 2 degradation is dependent on JNK-mediated phosphorylation ► Phosphorylation results in recruitment of the E3 Huwe1 leading to Mfn2 degradation ► This enhances mitochondrial fragmentation potentially linking it to cell death