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

Brunelle, JK; Shroff, EH; Perlman, H; Strasser, A; Moraes, CT; Flavell, RA; Danial, NN; Keith, B; Thompson, CB; Chandel, NS

Author(s): Brunelle, JK; Shroff, EH; Perlman, H; Strasser, A; Moraes, CT; Flavell, RA; Danial, NN; Keith, B; Thompson, CB; Chandel, NS;
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
Publisher's Version: https://doi.org/10.1128/MCB.01535-06
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Creation Date: 2007-02-01 12:00:00