Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death
Details
Publication Year 2007-02, Volume 27, Issue #4, Page 1222-1235
Journal Title
MOLECULAR AND CELLULAR BIOLOGY
Publication Type
Journal Article
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 1 beta, 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.
Publisher
AMER SOC MICROBIOLOGY
Keywords
BCL-2 FAMILY-MEMBERS; FACTOR-INDEPENDENT SURVIVAL; STRESS-INDUCED APOPTOSIS; BH3-ONLY PROTEINS; CYTOCHROME-C; OXYGEN DEPRIVATION; ANTIAPOPTOTIC PROPERTIES; MITOCHONDRIAL APOPTOSIS; MICE LACKING; BH3 DOMAINS
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Creation Date: 2007-02-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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