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Molecular and Cellular Biology, February 2007, p. 1222-1235, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01535-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Loss of Mcl-1 Protein and Inhibition of Electron Transport Chain Together Induce Anoxic Cell Death{triangledown} ,{dagger}

Joslyn K. Brunelle,1 Emelyn H. Shroff,1 Harris Perlman,2 Andreas Strasser,3 Carlos T. Moraes,4 Richard A. Flavell,5 Nika N. Danial,6 Brian Keith,7 Craig B. Thompson,7 and Navdeep S. Chandel1*

Department of Medicine and Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611,1 Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri 63104,2 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia,3 Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136,4 Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520,5 Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,6 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191047

Received 17 August 2006/ Returned for modification 11 October 2006/ Accepted 27 November 2006

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 1ß, 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.

* Corresponding author. Mailing address: McGaw Pavilion, 240 East Huron Avenue, M-334, Northwestern University Medical School, Chicago, IL 60611. Phone: (312) 503-2549. Fax: (312) 908-4650. E-mail: nav{at}northwestern.edu.

{triangledown} Published ahead of print on 4 December 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2007, p. 1222-1235, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01535-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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