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Vol. 18, Issue 11, 4681-4689, November 2007

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Adenine Nucleotide (ADP/ATP) Translocase 3 Participates in the Tumor Necrosis Factor–induced Apoptosis of MCF-7 Cells

Ziqiang Yang^*, Wei Cheng, Lixin Hong, Wanze Chen, Yanhai Wang, Shengcai Lin, Jiahuai Han, Huamin Zhou, and Jun Gu^*

*National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, China; The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Submitted December 29, 2006; Revised August 24, 2007; Accepted September 5, 2007
Monitoring Editor: John Cleveland

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 (TNF-)-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-–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-–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.

Address correspondence to: Huamin Zhou (huaminzhou{at}xmu.edu.cn) or Jun Gu (gj{at}pku.edu.cn)

Abbreviations used: ANT, adenine nucleotide translocase; MPT, mitochondrial permeability transition; TNF, tumor necrosis factor.

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