Cystamine induces AIF-mediated apoptosis through glutathione depletion

Sung Yup Cho, Jin Haeng Lee, Mi kyeong Ju, Eui Man Jeong, Hyo Jun Kim, Jisun Lim, Seungun Lee, Nam Hyuk Cho, Hyun Ho Park, Kihang Choi, Ju Hong Jeon, In Gyu Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)619-631
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1853
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

Fingerprint

Cystamine
Apoptosis Inducing Factor
Glutathione
Apoptosis
Cysteamine
Neurodegenerative Diseases
Cell Death
Glutamate-Cysteine Ligase
Unfolded Protein Response
Cell Line
Transglutaminases
Aptitude
Huntington Disease
Caspases

Keywords

  • Apoptosis-inducing factor
  • Caspase-independent cell death
  • Cystamine
  • Cysteamine
  • Glutathione
  • Nuclear translocation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Cho, S. Y., Lee, J. H., Ju, M. K., Jeong, E. M., Kim, H. J., Lim, J., ... Kim, I. G. (2015). Cystamine induces AIF-mediated apoptosis through glutathione depletion. Biochimica et Biophysica Acta - Molecular Cell Research, 1853(3), 619-631. https://doi.org/10.1016/j.bbamcr.2014.12.028

Cystamine induces AIF-mediated apoptosis through glutathione depletion. / Cho, Sung Yup; Lee, Jin Haeng; Ju, Mi kyeong; Jeong, Eui Man; Kim, Hyo Jun; Lim, Jisun; Lee, Seungun; Cho, Nam Hyuk; Park, Hyun Ho; Choi, Kihang; Jeon, Ju Hong; Kim, In Gyu.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1853, No. 3, 01.03.2015, p. 619-631.

Research output: Contribution to journalArticle

Cho, SY, Lee, JH, Ju, MK, Jeong, EM, Kim, HJ, Lim, J, Lee, S, Cho, NH, Park, HH, Choi, K, Jeon, JH & Kim, IG 2015, 'Cystamine induces AIF-mediated apoptosis through glutathione depletion', Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1853, no. 3, pp. 619-631. https://doi.org/10.1016/j.bbamcr.2014.12.028
Cho, Sung Yup ; Lee, Jin Haeng ; Ju, Mi kyeong ; Jeong, Eui Man ; Kim, Hyo Jun ; Lim, Jisun ; Lee, Seungun ; Cho, Nam Hyuk ; Park, Hyun Ho ; Choi, Kihang ; Jeon, Ju Hong ; Kim, In Gyu. / Cystamine induces AIF-mediated apoptosis through glutathione depletion. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2015 ; Vol. 1853, No. 3. pp. 619-631.
@article{e25b4a3fb2c74cc8b3243031704b1ab9,
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.",
keywords = "Apoptosis-inducing factor, Caspase-independent cell death, Cystamine, Cysteamine, Glutathione, Nuclear translocation",
author = "Cho, {Sung Yup} and Lee, {Jin Haeng} and Ju, {Mi kyeong} and Jeong, {Eui Man} and Kim, {Hyo Jun} and Jisun Lim and Seungun Lee and Cho, {Nam Hyuk} and Park, {Hyun Ho} and Kihang Choi and Jeon, {Ju Hong} and Kim, {In Gyu}",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.bbamcr.2014.12.028",
language = "English",
volume = "1853",
pages = "619--631",
journal = "Biochimica et Biophysica Acta - Molecular Cell Research",
issn = "0167-4889",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Cystamine induces AIF-mediated apoptosis through glutathione depletion

AU - Cho, Sung Yup

AU - Lee, Jin Haeng

AU - Ju, Mi kyeong

AU - Jeong, Eui Man

AU - Kim, Hyo Jun

AU - Lim, Jisun

AU - Lee, Seungun

AU - Cho, Nam Hyuk

AU - Park, Hyun Ho

AU - Choi, Kihang

AU - Jeon, Ju Hong

AU - Kim, In Gyu

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Apoptosis-inducing factor

KW - Caspase-independent cell death

KW - Cystamine

KW - Cysteamine

KW - Glutathione

KW - Nuclear translocation

UR - http://www.scopus.com/inward/record.url?scp=84920747583&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920747583&partnerID=8YFLogxK

U2 - 10.1016/j.bbamcr.2014.12.028

DO - 10.1016/j.bbamcr.2014.12.028

M3 - Article

C2 - 25549939

AN - SCOPUS:84920747583

VL - 1853

SP - 619

EP - 631

JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

SN - 0167-4889

IS - 3

ER -