{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T08:48:05Z","timestamp":1762159685825},"reference-count":82,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2001,12,20]],"date-time":"2001-12-20T00:00:00Z","timestamp":1008806400000},"content-version":"vor","delay-in-days":188,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2001,6,15]]},"abstract":"<jats:p>Compromised mitochondrial energy metabolism and oxidative stress have been associated with the pathophysiology of Parkinson's disease. Our previous experiments exemplified the importance of GSH in the protection of neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase\/complex\u2003II. This study further defines the role of oxidative stress during energy inhibition and begins to unravel the mechanisms by which GSH and other antioxidants may contribute to cell survival. Treatment of mesencephalic cultures with 10\u2003\u00b5<jats:sc>m<\/jats:sc>buthionine sulfoximine for 24\u2003h depleted total GSH by 60%, whereas 3\u2003h exposure to 5\u2003m<jats:sc>m<\/jats:sc>3\u2010amino\u20101,2,4\u2010triazole irreversibly inactivated catalase activity by 90%. Treatment of GSH\u2010depleted cells with malonate (40\u2003m<jats:sc>m<\/jats:sc>) for 6, 12 or 24\u2003h both potentiated and accelerated the time course of malonate toxicity, however, inhibition of catalase had no effect. In contrast, concomitant treatment with buthionine sulfoximine plus 3\u2010amino\u20101,2,4\u2010triazole in the presence of malonate significantly potentiated toxicity over that observed with malonate plus either inhibitor alone. Consistent with these findings, GSH depletion enhanced malonate\u2010induced reactive oxygen species generation prior to the onset of toxicity. These findings demonstrate that early generation of reactive oxygen species during mitochondrial inhibition contributes to cell damage and that GSH serves as a first line of defense in its removal. Pre\u2010treatment of cultures with 400\u2003\u00b5<jats:sc>m<\/jats:sc>ascorbate protected completely against malonate toxicity (50\u2003m<jats:sc>m<\/jats:sc>, 12\u2003h), whereas treatment with 1\u2003m<jats:sc>m<\/jats:sc>Trolox provided partial protection. Protein\u2013GSH mixed disulfide formation during oxidative stress has been suggested to either protect vulnerable protein thiols or conversely to contribute to toxicity. Malonate exposure (50\u2003m<jats:sc>m<\/jats:sc>) for 12\u2003h resulted in a modest increase in mixed disulfide formation. However, exposure to the protective combination of ascorbate plus malonate increased membrane bound protein\u2013GSH mixed disulfides three\u2010fold. Mixed disulfide levels returned to baseline by 72\u2003h of recovery indicating the reversible nature of this formation. These results demonstrate an early role for oxidative events during mitochondrial impairment and stress the importance of the glutathione system for removal of reactive oxygen species. Catalase may serve as a secondary defense as the glutathione system becomes limiting. These findings also suggest that protein\u2013GSH mixed disulfide formation under these circumstances may play a protective role.<\/jats:p>","DOI":"10.1046\/j.1471-4159.2001.00355.x","type":"journal-article","created":{"date-parts":[[2003,3,12]],"date-time":"2003-03-12T06:55:21Z","timestamp":1047452121000},"page":"1496-1507","source":"Crossref","is-referenced-by-count":22,"title":["Hydrogen peroxide removal and glutathione mixed disulfide formation during metabolic inhibition in mesencephalic cultures"],"prefix":"10.1111","volume":"77","author":[{"given":"Julie","family":"Ehrhart","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail D.","family":"Zeevalk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2001,12,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(84)05016-3"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0721170.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(87)90087-6"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/116.6.1451"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/1357-2725(95)00019-l"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/81834"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(91)90311-T"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3940(98)00539-4"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(79)80609-2"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1340707"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(82)90393-8"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(83)90014-X"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.9.1007"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2981433"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1979.59.3.527"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb09789.x"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(92)90530-A"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00906a038"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0732310.x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.10.4890"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1006\/exer.1993.1111"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90274-O"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410350107"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320719"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-5730-8_24"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00064a021"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(80)90139-6"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(85)90232-0"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410370604"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715769609149066"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00995149"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420520405"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(82)90044-X"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.5.1913"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.11.5093"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1996.9858"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320714"},{"key":"e_1_2_7_39_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1523\/JNEUROSCI.20-01-00001.2000","article-title":"Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3\u2010nitropropionic acid, and 1\u2010methyl\u20104\u2010phenyl\u20101,2,5,6\u2010tetrahydropyridine","volume":"20","author":"Klivenyi P.","year":"2000","journal-title":"J. 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