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

JK Brunelle, EH Shroff, H Perlman… - … and cellular biology, 2007 - Taylor & Francis
JK Brunelle, EH Shroff, H Perlman, A Strasser, CT Moraes, RA Flavell, NN Danial, B Keith…
Molecular and cellular biology, 2007Taylor & Francis
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 1β, 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 …
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 1β, 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 ([rho0] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho0] cells, in contrast to [rho] cells, did not die under anoxia. However, [rho0] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-XL/Bcl-2 proteins. These results indicate that [rho0] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-XL/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-XL/Bcl-2 proteins.
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