Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease
| Autor: | Cecilia R Giulivi, Connie Hung, Sarah Wong, Eleonora Napoli, Prithvi R. Bomdica, Catherine Ross-Inta |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Mitochondrial DNA Mutant Nerve Tissue Proteins Oxidative phosphorylation Mitochondrion Biology DNA Mitochondrial Medical and Health Sciences Human mitochondrial genetics Oxidative Phosphorylation Mice Huntington's disease Genetics Huntingtin Protein medicine Animals Humans Oxidoreductases Acting on Sulfur Group Donors Allele Molecular Biology Genetics (clinical) Neurons Genetics & Heredity Nuclear Proteins Cell Differentiation Articles DNA General Medicine Biological Sciences medicine.disease Molecular biology Corpus Striatum Mitochondria Mitochondrial Huntington Disease Mutation Trinucleotide Repeat Expansion |
| Zdroj: | Human molecular genetics, vol 22, iss 5 Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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