Mitochondrial hyperfusion promotes NF-κB activation via the mitochondrial E3 ligase MULAN

FEBS J. 2014 Jul;281(14):3095-112. doi: 10.1111/febs.12846. Epub 2014 Jun 2.


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.

Keywords: MULAN; NF-κB; SIMH; TRAF2; mitochondrial dynamics.

Publication types

  • Editorial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dynamins
  • GTP Phosphohydrolases / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / physiology*
  • Mitochondrial Dynamics / physiology*
  • Mitochondrial Proteins / metabolism
  • NF-kappa B / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitination


  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • MARCHF5 protein, human
  • MUL1 protein, human
  • Ubiquitin-Protein Ligases
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dynamins