Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death
David S McClintock, Matthew T Santore, Vivian Y Lee, Joslyn Brunelle, G R Scott Budinger, Wei-Xing Zong, Craig B Thompson, Nissim Hay, Navdeep S Chandel, David S McClintock, Matthew T Santore, Vivian Y Lee, Joslyn Brunelle, G R Scott Budinger, Wei-Xing Zong, Craig B Thompson, Nissim Hay, Navdeep S Chandel
Abstract
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-X(L) prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-X(L) 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 F(1)F(0)-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-X(L), cells devoid of mitochondrial DNA (rho degrees 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.
Figures
![FIG. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856001.jpg)
![FIG. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856002.jpg)
![FIG. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856003.jpg)
![FIG. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856004.jpg)
![FIG. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856005.jpg)
![FIG. 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856006.jpg)
![FIG. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/134234/bin/mb0120856007.jpg)
Source: PubMed