Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death

Mol Cell Biol. 2007 Feb;27(4):1222-35. doi: 10.1128/MCB.01535-06. Epub 2006 Dec 4.


How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1beta, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(-)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho(-)] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X(L)/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X(L)/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X(L)/Bcl-2 proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects
  • Animals
  • Caspase 9 / deficiency
  • Caspase 9 / metabolism
  • Cell Death / drug effects
  • Cell Hypoxia / drug effects
  • Cytochromes b / genetics
  • DNA, Mitochondrial / metabolism
  • Electron Transport / drug effects
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Glycolysis / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism
  • Mice
  • Models, Biological
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / deficiency*
  • Neoplasm Proteins / metabolism
  • Oxygen / pharmacology
  • Protein Structure, Tertiary / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / deficiency*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism
  • Sequence Deletion
  • Tumor Cells, Cultured


  • DNA, Mitochondrial
  • Hypoxia-Inducible Factor 1
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Cytochromes b
  • Caspase 9
  • Oxygen