Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members.
Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim(-/-)/Puma(-/-) MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death.
Snyder
Colleen M
CM
Department of Medicine, Northwestern University Medical School, Chicago, Illinois, United States of America.
Shroff
Emelyn H
EH
Liu
Jing
J
Chandel
Navdeep S
NS
D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D005810:Multigene Family; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009569:Nitric Oxide / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D045222:Electron Transport Chain Complex Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D045304:Cytochromes c; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D053453:Caspase 9