title: Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death.
abstract: 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.
authors.affiliation: Department of Medicine, Northwestern University Medical School, 240 East Huron Avenue, Chicago, IL 60611, USA.
authors.forename: Joslyn K
authors.initials: JK
authors.lastname: Brunelle
authors.forename: Emelyn H
authors.initials: EH
authors.lastname: Shroff
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D053453:Caspase 9 / Q000172:deficiency / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045303:Cytochromes b / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
chemical_list: D004272:DNA, Mitochondrial; D051793:Hypoxia-Inducible Factor 1; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D045303:Cytochromes b; D053453:Caspase 9; D010100:Oxygen