title: Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease.
abstract: A number of studies have been conducted that link mitochondrial dysfunction (MD) to Huntington's disease (HD); however, contradicting results had resulted in a lack of a clear mechanism that links expression of mutant Huntingtin protein and MD. Mouse homozygous (HM) and heterozygous (HT) mutant striatal cells with two or one allele encoding for a mutant huntingtin protein with 111 polyGln repeats showed a significant impairment of the mitochondrial disulfide relay system (MDRS). This system (consisting of two proteins, Gfer and Mia40) is involved in the mitochondrial import of Cys-rich proteins. The Gfer-to-Mia40 ratio was significantly altered in HM cells compared with controls, along with the expression of mitochondrial proteins considered substrates of the MDRS. In progenitors and differentiated neuron-like HM cells, impairment of MDRS were accompanied by deficient oxidative phosphorylation, Complex I, IV and V activities, decreased mtDNA copy number and transcripts, accumulation of mtDNA deletions and changes in mitochondrial morphology, consistent with other MDRS-deficient biological models, thus providing a framework for the energy deficits observed in this HD model. The majority (>90%) of the mitochondrial outcomes exhibited a gene-dose dependency with the expression of mutant Htt. Finally, decreases in the mtDNA copy number, along with the accumulation of mtDNA deletions, provide a mechanism for the progressive neurodegeneration observed in HD patients.
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.forename: Connie
authors.initials: C
authors.lastname: Hung
authors.forename: Catherine
authors.initials: C
authors.lastname: Ross-Inta
authors.forename: Prithvi
authors.initials: P
authors.lastname: Bomdica
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003342:Corpus Striatum; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D010085:Oxidative Phosphorylation; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D050862:Oxidoreductases Acting on Sulfur Group Donors; C551231:GFER protein, mouse