Regulation of the activation of nuclear factor kappaB by mitochondrial respiratory function: evidence for the reactive oxygen species-dependent and -independent pathways

Antioxid Redox Signal. 2002 Dec;4(6):945-55. doi: 10.1089/152308602762197489.


Mitochondrial respiratory function regulates the redox status of cells, which, in turn, can control the activation of transcription factors. However, how mitochondria accomplish this modulation is not completely understood. Using the human myelogenous leukemia cells ML-1a, respiration-deficient clone 19 derived from ML-1a, and reconstituted clones, we demonstrated the role of respiratory function in the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Constitutive activation of NF-kappaB and AP-1 was observed in clone 19, but not in ML-1a, and the constitutive activation observed in clone 19 was completely inhibited in reconstituted clones that have functional mitochondria. Additionally, tumor necrosis factor (TNF)-induced activation of NF-kappaB and AP-1 observed in ML-1a was greatly reduced in clone 19. These results indicate that mitochondrial respiratory function regulates TNF-induced and constitutive activation of NF-kappaB and AP-1. We investigated the roles of reactive oxygen species in NF-kappaB activation. Generation of superoxide detected by hydroethidine, but not hydrogen peroxide detected by dehydrorhodamine 123, was transiently increased by TNF in both of the cells. The antioxidant, pyrrolidine dithiocarbamate, reduced TNF-induced, but not the constitutive, NF-kappaB activation. These results indicate that the increase in superoxide generation might be involved in TNF-induced, but not in constitutive, NF-kappaB activation. Our results thus demonstrate the involvement of mitochondrial respiratory function in the activation of reactive oxygen species-dependent and -independent pathways for NF-kappaB activation.

MeSH terms

  • 2-Methoxyestradiol
  • Cell Respiration / physiology*
  • Cloning, Molecular
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Ethidium / metabolism
  • Flow Cytometry
  • Humans
  • Hydrogen Peroxide / analysis
  • Hydrogen Peroxide / pharmacology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Mitochondria / physiology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Pyrrolidines / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Superoxides / analysis
  • Thiocarbamates / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Tumor Cells, Cultured


  • NF-kappa B
  • Pyrrolidines
  • Reactive Oxygen Species
  • Thiocarbamates
  • Transcription Factor AP-1
  • Superoxides
  • pyrrolidine dithiocarbamic acid
  • Estradiol
  • 2-Methoxyestradiol
  • Hydrogen Peroxide
  • Ethidium