Mitochondrial hyperfusion promotes NF-κB activation via the mitochondrial E3 ligase MULAN
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Naima Zemirli1, Marie Pourcelot, Gorbatchev Ambroise
1INSERM, UMR_S 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud P11, Orsay, France; Equipe Labellisée Ligue contre le Cancer, Villejuif, France.
Abstract:
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.
Insights
Mitochondrial dynamics, specifically hyperfusion, activate the NF-κB pathway via the MULAN E3 ligase. This suggests mitochondria convert stress signals into cellular responses, impacting immune signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Mitochondria are dynamic organelles shaped by fusion and fission processes.
- The functional significance of mitochondrial fusion, beyond mtDNA maintenance, remains largely unexplored.
- Nuclear factor-kappa B (NF-κB) is a critical transcription factor involved in immune responses and cellular stress.
Discussion:
- Enforced mitochondrial hyperfusion activates NF-κB signaling through a pathway involving TAK1, IKK, and the mitochondrial E3 ubiquitin ligase MULAN.
- MULAN's E3 ligase activity, specifically its RING domain and interaction with TRAF2, is crucial for NF-κB activation.
- Stress-induced mitochondrial hyperfusion (SIMH) physiologically correlates with NF-κB activation, highlighting a role for mitochondrial dynamics in immune signaling.
Key Insights:
- Mitochondrial hyperfusion, induced experimentally or physiologically, triggers NF-κB activation.
- The mitochondrial E3 ligase MULAN acts as a key mediator, linking mitochondrial dynamics to NF-κB signaling.
- TRAF2 is implicated as an ubiquitylated signaling transmitter in the MULAN-mediated NF-κB activation pathway during SIMH.
Outlook:
- Investigating the precise mechanisms of MULAN-TRAF2 interaction and ubiquitylation.
- Exploring the therapeutic potential of modulating mitochondrial dynamics in inflammatory diseases.
- Further elucidating the role of mitochondrial stress responses in innate and adaptive immunity.