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.