{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:49:22Z","timestamp":1789519762583,"version":"build-2803163510"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":175,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:p>Valproic acid (VPA) is widely used to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy, but potentially causes idiosyncratic liver injury. Alpers\u2010Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity. However, the mechanistic link of this clinical mystery remains unknown. Here, fibroblasts from 2 AHS patients were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to hepatocyte\u2010like cells (AHS iPSCs\u2010Hep). Both AHS iPSCs\u2010Hep are more sensitive to VPA\u2010induced mitochondrial\u2010dependent apoptosis than controls, showing more activated caspase\u20109 and cytochrome <jats:italic toggle=\"yes\">c<\/jats:italic> release. Strikingly, levels of both soluble and oligomeric optic atrophy 1, which together keep cristae junctions tight, are reduced in AHS iPSCs\u2010Hep. Furthermore, POLG mutation cells show reduced POLG expression, mitochondrial DNA (mtDNA) amount, mitochondrial adenosine triphosphate production, as well as abnormal mitochondrial ultrastructure after differentiation to hepatocyte\u2010like cells. Superoxide flashes, spontaneous bursts of superoxide generation, caused by opening of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs\u2010Hep. Moreover, the mPTP inhibitor, cyclosporine A, rescues VPA\u2010induced apoptotic sensitivity in AHS iPSCs\u2010Hep. This result suggests that targeting mPTP opening could be an effective method to prevent hepatotoxicity by VPA in AHS patients. In addition, carnitine or <jats:italic toggle=\"yes\">N<\/jats:italic>\u2010acetylcysteine, which has been used in the treatment of VPA\u2010induced hepatotoxicity, is able to rescue VPA\u2010induced apoptotic sensitivity in AHS iPSCs\u2010Hep. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: AHS iPSCs\u2010Hep are more sensitive to the VPA\u2010induced mitochondrial\u2010dependent apoptotic pathway, and this effect is mediated by mPTP opening. Toxicity models in genetic diseases using iPSCs enable the evaluation of drugs for therapeutic targets. (H<jats:sc>epatology<\/jats:sc> 2015;61:1730\u20101739)<\/jats:p>","DOI":"10.1002\/hep.27712","type":"journal-article","created":{"date-parts":[[2015,1,20]],"date-time":"2015-01-20T22:38:54Z","timestamp":1421793534000},"page":"1730-1739","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":93,"title":["Valproic acid\u2010induced hepatotoxicity in alpers syndrome is associated with mitochondrial permeability transition pore opening\u2010dependent apoptotic sensitivity in an induced pluripotent stem cell model"],"prefix":"10.1097","volume":"61","author":[{"given":"Shengbiao","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"},{"name":"University of Science and Technology of China,Hefei,Anhui,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"},{"name":"University of Science and Technology of China,Hefei,Anhui,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongfu","family":"Ying","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshi","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Long","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajiang","family":"Qin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duanqing","family":"Pei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of 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