IDH2 deficiency exacerbates acetaminophen hepatotoxicity in mice via mitochondrial dysfunction-induced apoptosis
DC Field | Value | Language |
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dc.contributor.author | Kim, Hyunjin | - |
dc.contributor.author | Lee, Jin Hyup | - |
dc.contributor.author | Park, Jeen-Woo | - |
dc.date.accessioned | 2021-09-01T07:15:14Z | - |
dc.date.available | 2021-09-01T07:15:14Z | - |
dc.date.created | 2021-06-19 | - |
dc.date.issued | 2019-09-01 | - |
dc.identifier.issn | 0925-4439 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/62935 | - |
dc.description.abstract | Acetaminophen (APAP)-induced hepatotoxicity is a major factor in liver failure and its toxicity is associated with the generation of reactive oxygen species (ROS), decreased levels of reduced glutathione (GSH) and overall oxidative stress. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) was demonstrated as an essential enzyme for mitochondria to maintain their antioxidant system by generating NADPH, which is an essential reducing equivalent for GSH turnover in mitochondria. Here, we investigated the role of IDH2 in APAP-induced liver injury with IDH2 deficient (idh2(-/-)) mice. Hepatotoxicity was promoted through apoptotic cell death following APAP administration in IDH2 deficient hepatocytes compared to that in wild-type hepatocytes. Apoptosis was found to result from the induction of ER stress and mitochondrial dysfunction as shown by the blocking the effect of phenylbutyrate and Mdivil, respectively. In addition, mito-TEMPO, a scavenger of mitochondrial ROS, was seen to ameliorate APAP-induced hepatotoxicity in idh2(-/-) mice. In conclusion, IDH2 deficiency leads to a fundamental shortage of GSH that increases susceptibility to ROS generation and oxidative stress. This leads to excessive mitochondrial dysfunction and ER stress induction in response to APAP administration. Our study provides further evidence that IDH2 has a protective role against APAP-induced liver injury and emphasizes the importance of the elaborate linkages and functions of the antioxidant system in liver health. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | ELSEVIER | - |
dc.subject | NADP(+)-DEPENDENT ISOCITRATE DEHYDROGENASE | - |
dc.subject | ACUTE LIVER-FAILURE | - |
dc.subject | OXIDATIVE STRESS | - |
dc.subject | AUTOPHAGY PROTECTS | - |
dc.subject | OXIDANT STRESS | - |
dc.subject | CELL-DEATH | - |
dc.subject | ACTIVATION | - |
dc.subject | MODULATION | - |
dc.subject | GENERATION | - |
dc.subject | TOXICITY | - |
dc.title | IDH2 deficiency exacerbates acetaminophen hepatotoxicity in mice via mitochondrial dysfunction-induced apoptosis | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, Jin Hyup | - |
dc.identifier.doi | 10.1016/j.bbadis.2019.05.012 | - |
dc.identifier.scopusid | 2-s2.0-85066086256 | - |
dc.identifier.wosid | 000476965200022 | - |
dc.identifier.bibliographicCitation | BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v.1865, no.9, pp.2333 - 2341 | - |
dc.relation.isPartOf | BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | - |
dc.citation.title | BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | - |
dc.citation.volume | 1865 | - |
dc.citation.number | 9 | - |
dc.citation.startPage | 2333 | - |
dc.citation.endPage | 2341 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Biophysics | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Biophysics | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.subject.keywordPlus | NADP(+)-DEPENDENT ISOCITRATE DEHYDROGENASE | - |
dc.subject.keywordPlus | ACUTE LIVER-FAILURE | - |
dc.subject.keywordPlus | OXIDATIVE STRESS | - |
dc.subject.keywordPlus | AUTOPHAGY PROTECTS | - |
dc.subject.keywordPlus | OXIDANT STRESS | - |
dc.subject.keywordPlus | CELL-DEATH | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | MODULATION | - |
dc.subject.keywordPlus | GENERATION | - |
dc.subject.keywordPlus | TOXICITY | - |
dc.subject.keywordAuthor | IDH2 | - |
dc.subject.keywordAuthor | Acetaminophen | - |
dc.subject.keywordAuthor | ER stress | - |
dc.subject.keywordAuthor | Mitochondrial dysfunction | - |
dc.subject.keywordAuthor | Reactive oxygen species | - |
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