title: IDH2 deficiency promotes mitochondrial dysfunction and dopaminergic neurotoxicity: implications for Parkinson's disease.
abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and its pathogenesis is under intense investigation. Substantial evidence indicates that mitochondrial dysfunction and oxidative stress play central roles in the pathophysiology of PD, through activation of mitochondria-dependent apoptotic molecular pathways. Several mitochondrial internal regulating factors act to maintain mitochondrial function. However, the mechanism by which these internal regulating factors contribute to mitochondrial dysfunction in PD remains elusive. One of these factors, mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2), has been implicated in the regulation of mitochondrial redox balance and reduction of oxidative stress-induced cell injury. Here we report that IDH2 regulates mitochondrial dysfunction and cell death in MPP(+)/MPTP-induced DA neuronal cells, and in a mouse model of PD. Down-regulation of IDH2 increased DA neuron sensitivity to MPP(+); lowered IDH2 levels facilitated induction of apoptotic cell death due to elevated mitochondrial oxidative stress. Deficient IDH2 also promoted loss of DA SNpc neurons in an MPTP mouse model of PD. Interestingly, Mito-TEMPO, a mitochondrial ROS-specific scavenger, protected degeneration of SNpc DA neurons in the MPTP model of PD. These findings demonstrate that IDH2 contributes to degeneration of the DA neuron in the neurotoxin model of PD and establish IDH2 as a molecular target of potential therapeutic significance for this disabling neurological illness.
authors.affiliation: a School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences , Kyungpook National University , Taegu , Korea ;
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: a School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences , Kyungpook National University , Taegu , Korea ;
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: a School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences , Kyungpook National University , Taegu , Korea ;
authors.forename: Hanvit
authors.initials: H
authors.lastname: Cha
authors.affiliation: a School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences , Kyungpook National University , Taegu , Korea ;
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Kim
authors.affiliation: b Department of Food and Biotechnology , Korea University , Sejong , Korea ;|c Institutes of Natural Sciences, Korea University , Sejong , Korea.
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.affiliation: a School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences , Kyungpook National University , Taegu , Korea ;
authors.forename: Jeen-Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D007521:Isocitrate Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse
keywords: Antioxidant enzyme; Parkinson’s disease; apoptosis; mitochondria; oxidative stress