Mitochondrial hyperfusion promotes NF-κB activation via the mitochondrial E3 ligase MULAN.
Mitochondria are dynamic organelles with a morphology resulting from the balance between two opposing processes: fusion and fission. Little is known about the function of mitochondrial fusion, beside its role in the maintenance of mitochondrial DNA. We report here that enforced mitochondrial hyperfusion, due to the expression of a dominant-negative mutant of Drp1 or of MARCH5, promotes NF-κB activation in a TAK1- and IKK-dependent manner, through the mitochondrial E3 ubiquitin ligase MULAN. The capability of MULAN to activate NF-κB depends on its RING domain and on the E3 ubiquitin ligase TRAF2. Under physiological conditions, stress-induced mitochondrial hyperfusion (SIMH) is also accompanied by NF-κB activation, and the prevention of SIMH or the knockdown of MULAN impairs NF-κB activation. During SIMH, MULAN forms a complex with TRAF2 and modulates its ubiquitylation, signifying that TRAF2 may serve as an ubiquitylated transmitter of NF-κB signaling in this pathway. Our results suggest that mitochondria, through their dynamics, convert stress signals into a cell response leading to NF-κB activation.
['Zemirli|Naima|N|', 'Pourcelot|Marie|M|', 'Ambroise|Gorbatchev|G|', 'Hatchi|Emeline|E|', 'Vazquez|Aimé|A|', 'Arnoult|Damien|D|']
D000818:Animals D034281:Dynamins D020558:GTP Phosphohydrolases D055785:Gene Knockdown Techniques D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D008565:Membrane Proteins D051379:Mice D008869:Microtubule-Associated Proteins D008928:Mitochondria D063154:Mitochondrial Dynamics D024101:Mitochondrial Proteins D016328:NF-kappa B D015398:Signal Transduction D047992:TNF Receptor-Associated Factor 2 D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination
NF-κB MULAN TRAF2 SIMH mitochondrial dynamics