title: Cystamine induces AIF-mediated apoptosis through glutathione depletion.
abstract: Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death.
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Sung-Yup
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Mi-kyeong
authors.initials: MK
authors.lastname: Ju
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Eui Man
authors.initials: EM
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Hyo-Jun
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Seungun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Nam-Hyuk
authors.initials: NH
authors.lastname: Cho
authors.affiliation: Graduate School of Biochemistry, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Park
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.affiliation: Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea. Electronic address: igkim@snu.ac.kr.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D003538:Cystamine / Q000494:pharmacology*; D004381:Duodenal Ulcer / Q000378:metabolism / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051033:Apoptosis Inducing Factor; D017382:Reactive Oxygen Species; D005978:Glutathione; D003538:Cystamine
keywords: Apoptosis-inducing factor; Caspase-independent cell death; Cystamine; Cysteamine; Glutathione; Nuclear translocation