Adenine nucleotide (ADP/ATP) translocase 3 participates in the tumor necrosis factor induced apoptosis of MCF-7 cells

Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, becau...

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Published in:Molecular biology of the cell 2007-11, Vol.18 (11), p.4681-4689
Main Authors: Yang, Ziqiang, Cheng, Wei, Hong, Lixin, Chen, Wanze, Wang, Yanhai, Lin, Shengcai, Han, Jiahuai, Zhou, Huamin, Gu, Jun
Format: Article
Language:English
Subjects:
Adenine Nucleotide Translocator 3 - genetics
Adenine Nucleotide Translocator 3 - metabolism
Adenosine Triphosphate - metabolism
Apoptosis - drug effects
Cell Line, Tumor
Cytochromes c - metabolism
Humans
Mitochondria - drug effects
Mitochondria - metabolism
Mutation - genetics
Oxidative Stress
Reactive Oxygen Species - metabolism
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, because hepatocytes isolated from ANT knockout and wild-type mice are equally sensitive to TNF- and Fas-induced apoptosis. In a screen for genes required for tumor necrosis factor alpha (TNF-alpha)-induced apoptosis in MCF-7 human breast cancer cells using retrovirus insertion-mediated random mutagenesis, we discovered that the ANT3 gene is involved in TNF-alpha-induced cell death in MCF-7 cells. We further found that ANT3 is selectively required for TNF- and oxidative stress-induced cell death in MCF-7 cells, but it is dispensable for cell death induced by several other inducers. This data supplements previous data obtained from ANT knockout studies, indicating that ANT is involved in some apoptotic processes. We found that the resistance to TNF-alpha-induced apoptosis observed in ANT3 mutant (ANT3(mut)) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release. It is not related to intracellular ATP levels or survival pathways, supporting a previous model in which ANT regulates mtPTP. Our study provides genetic evidence supporting a role of ANT in apoptosis and suggests that the involvement of ANT in cell death is cell type- and stimulus-dependent.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E06-12-1161