title: Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death.
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.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60601-3010, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: McClintock
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Santore
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Lee
authors.forename: Joslyn
authors.initials: J
authors.lastname: Brunelle
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004579:Electron Transport / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D004317:Doxorubicin; D000255:Adenosine Triphosphate; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; D005947:Glucose; D010100:Oxygen