Defining the pathogenesis of human mtDNA mutations using a yeast model: The case of T8851C
| Autor: | Monika Wysocka-Kapcinska, Nadine Camougrand, Marie-France Giraud, Francis Haraux, Bénédicte Salin, Nahia Ezkurdia, Jean Velours, Jean-Paul di Rago, Roza Kucharczyk, Daniel Brèthes |
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| Přispěvatelé: | Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Mitochondrial DNA Molecular Sequence Data Mutant [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Mitochondrion medicine.disease_cause DNA Mitochondrial Biochemistry Oxidative Phosphorylation 03 medical and health sciences Oxygen Consumption 0302 clinical medicine Yeasts medicine Animals Humans Point Mutation Amino Acid Sequence 030304 developmental biology 0303 health sciences Mutation ATP synthase Point mutation Mutagenesis Cell Biology Mitochondrial Proton-Translocating ATPases Yeast Mitochondria Mitochondrial Membranes Mutagenesis Site-Directed biology.protein 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Biochemistry and Cell Biology International Journal of Biochemistry and Cell Biology, Elsevier, 2013, 45 (1), pp.130-40. ⟨10.1016/j.biocel.2012.07.001⟩ |
| ISSN: | 1357-2725 |
| DOI: | 10.1016/j.biocel.2012.07.001⟩ |
| Popis: | International audience; More and more mutations are found in the mitochondrial DNA of various patients but ascertaining their pathogenesis is often difficult. Due to the conservation of mitochondrial function from yeast to humans, the unique ability of yeast to survive without production of ATP by oxidative phosphorylation, and the amenability of the yeast mitochondrial genome to site-directed mutagenesis, yeast is an excellent model for investigating the consequences of specific human mtDNA mutations. Here we report the construction of a yeast model of a point mutation (T8851C) in the mitochondrially-encoded subunit a/6 of the ATP synthase that has been associated with bilateral striatal lesions, a group of rare human neurological disorders characterized by symmetric degeneration of the corpus striatum. The biochemical consequences of this mutation are unknown. The T8851C yeast displayed a very slow growth phenotype on non-fermentable carbon sources, both at 28°C (the optimal temperature for yeast growth) and at 36°C. Mitochondria from T8851C yeast grown in galactose at 28°C showed a 60% deficit in ATP production. When grown at 36°C the rate of ATP synthesis was below 5% that of the wild-type, indicating that heat renders the mutation much more deleterious. At both growth temperatures, the mutant F(1)F(o) complex was correctly assembled but had only very weak ATPase activity (about 10% that of the control), both in mitochondria and after purification. These findings indicate that a block in the proton-translocating domain of the ATP synthase is the primary cause of the neurological disorder in the patients carrying the T8851C mutation. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. |
| Databáze: | OpenAIRE |
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