title: IDH2 deficiency impairs mitochondrial function in endothelial cells and endothelium-dependent vasomotor function.
abstract: Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) plays an essential role protecting cells against oxidative stress-induced damage. A deficiency in IDH2 leads to mitochondrial dysfunction and the production of reactive oxygen species (ROS) in cardiomyocytes and cancer cells. However, the function of IDH2 in vascular endothelial cells is mostly unknown. In this study the effects of IDH2 deficiency on mitochondrial and vascular function were investigated in endothelial cells. IDH2 knockdown decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II and III, which lead to increased mitochondrial superoxide. In addition, the levels of fission and fusion proteins (Mfn-1, OPA-1, and Drp-1) were significantly altered and MnSOD expression also was decreased by IDH2 knockdown. Furthermore, knockdown of IDH2 decreased eNOS phosphorylation and nitric oxide (NO) concentration in endothelial cells. Interestingly, treatment with Mito-TEMPO, a mitochondrial-specific superoxide scavenger, recovered mitochondrial fission-fusion imbalance and blunted mitochondrial superoxide production, and reduced the IDH2 knockdown-induced decrease in MnSOD expression, eNOS phosphorylation and NO production in endothelial cells. Endothelium-dependent vasorelaxation was impaired, and the concentration of bioavailable NO decreased in the aortic ring in IDH2 knockout mice. These findings suggest that IDH2 deficiency induces endothelial dysfunction through the induction of dynamic mitochondrial changes and impairment in vascular function.
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Jung-Bum
authors.initials: JB
authors.lastname: Park
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Harsha
authors.initials: H
authors.lastname: Nagar
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Endocrinology, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Shin Kwang
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Emergency ICU, Regional Emergency Center, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Jun Wan
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Food and Biotechnology, Korea University, Sejong 339-700, Republic of Korea.
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.affiliation: School of Life Sciences, College of Natural Science, Kyungpook National University, Taegu 702-701, Republic of Korea.
authors.forename: Jeen-Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Department of Neurology, School of Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea. Electronic address: nrsono@naver.com.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea. Electronic address: cskim@cnu.ac.kr.
authors.forename: Cuk-Seong
authors.initials: CS
authors.lastname: Kim
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics*; D010880:Piperidines / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase
keywords: IDH2; Mitochondria; OXPHOS complexes; ROS; eNOS