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Molecular and Cellular Biology, January 2002, p. 94-104, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.94-104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Bcl-2 Family Members and Functional Electron Transport Chain Regulate Oxygen Deprivation-Induced Cell Death

David S. McClintock,1 Matthew T. Santore,1 Vivian Y. Lee,1 Joslyn Brunelle,1 G. R. Scott Budinger,1 Wei-Xing Zong,2 Craig B. Thompson,2 Nissim Hay,3 and Navdeep S. Chandel1*

Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Medical School,1 Departments of Medicine and Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania,2 Department of Molecular Genetics, University of Illinois, Chicago, Illinois3

Received 6 June 2001/ Returned for modification 16 July 2001/ Accepted 9 October 2001

The mechanisms underlying cell death during oxygen deprivation are unknown. We report here a model for oxygen deprivation-induced apoptosis. The death observed during oxygen deprivation involves a decrease in the mitochondrial membrane potential, followed by the release of cytochrome c and the activation of caspase-9. Bcl-XL prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-XL to prevent cell death was dependent on allowing the import of glycolytic ATP into the mitochondria to generate an inner mitochondrial membrane potential through the F1F0-ATP synthase. In contrast, although activated Akt has been shown to inhibit apoptosis induced by a variety of apoptotic stimuli, it did not prevent cell death during oxygen deprivation. In addition to Bcl-XL, cells devoid of mitochondrial DNA ({rho}° cells) that lack a functional electron transport chain were resistant to oxygen deprivation. Further, murine embryonic fibroblasts from bax-/- bak-/- mice did not die in response to oxygen deprivation. These data suggest that when subjected to oxygen deprivation, cells die as a result of an inability to maintain a mitochondrial membrane potential through the import of glycolytic ATP. Proapoptotic Bcl-2 family members and a functional electron transport chain are required to initiate cell death in response to oxygen deprivation.

* Corresponding author. Mailing address: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, IL 60601-3010. Phone: (312) 908-8163. Fax: (312) 908-4650. E-mail: nav{at}northwestern.edu.

Molecular and Cellular Biology, January 2002, p. 94-104, Vol. 22, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.1.94-104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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