title: Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin.
abstract: Alterations of mitochondrial function may play a central role in neuronal death in Huntington's disease (HD). However, the molecular mechanisms underlying such functional deficits of mitochondria are not elucidated yet. We herein showed that the expression of two important constituents of mitochondrial complex II, the 30-kDa iron-sulfur (Ip) subunit and the 70-kDa FAD (Fp) subunit, was preferentially decreased in the striatum of HD patients compared with controls. We also examined several mitochondrial proteins in striatal neurons that were infected with lentiviral vectors coding for the N-terminus part of huntingtin (Htt) with either a pathological (Htt171-82Q) or physiological (Htt171-19Q) polyglutamine tract. Compared with Htt171-19Q, expression of Htt171-82Q preferentially decreased the levels of Ip and Fp subunits and affected the dehydrogenase activity of the complex. The Htt171-82Q-induced preferential loss of complex II was not associated with a decrease in mRNA levels, suggesting the involvement of a posttranscriptional mechanism. Importantly, the overexpression of either Ip or Fp subunit restored complex II levels and blocked mitochondrial dysfunction and striatal cell death induced by Htt171-82Q in striatal neurons. The present results strongly suggest that complex II defects in HD may be instrumental in striatal cell death.
authors.affiliation: URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot, MIRCen Program, Département de Recherches Médicales, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique (CEA), 91401 Orsay Cedex, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benchoua
authors.forename: Yaël
authors.initials: Y
authors.lastname: Trioulier
authors.forename: Diana
authors.initials: D
authors.lastname: Zala
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaillard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lefort
authors.forename: Noelle
authors.initials: N
authors.lastname: Dufour
authors.forename: Frederic
authors.initials: F
authors.lastname: Saudou
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Elalouf
authors.forename: Etienne
authors.initials: E
authors.lastname: Hirsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
mesh_terms: D017209:Apoptosis; D003342:Corpus Striatum / Q000166:cytology / Q000201:enzymology*; D015536:Down-Regulation; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000201:enzymology; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D014162:Transfection
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D021122:Protein Subunits; C097188:polyglutamine; D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase