Cystamine induces AIF-mediated apoptosis through glutathione depletion

Title
Cystamine induces AIF-mediated apoptosis through glutathione depletion
Author(s)
박현호조성엽[조성엽]이진행[이진행]주미경[주미경]정의만[정의만]김효준[김효준]임지선[임지선]이성은[이성은]조남혁[조남혁]최기항[최기항]전주홍[전주홍]김인규[김인규]
Keywords
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; HUNTINGTON-DISEASE; TRANSGLUTAMINASE 2; OXIDATIVE STRESS; CELL-DEATH; MICE; BRAIN; CYSTEAMINE; MODEL; INFLAMMATION
Issue Date
201503
Publisher
ELSEVIER SCIENCE BV
Citation
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v.1853, no.3, pp.619 - 631
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 gamma-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. (C) 2014 Elsevier B.V. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/33047http://dx.doi.org/10.1016/j.bbamcr.2014.12.028
ISSN
0167-4889
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이과대학 > 화학생화학부 > Articles
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