Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors
| Autor: | Paweł Grzmil, Martin Hrabé de Angelis, Michael Klinkenberg, Heinz D. Osiewacz, Suzana Gispert, Sebastian Koob, Georg Auburger, Ulrich Brandt, Dirk H. Busch, Michael A. Walter, Marina Jendrach, Andreas S. Reichert, Thure Adler, Stefan Dröse, Ilka Wittig, Andreas Zell, Finja Büchel, Michel Mittelbronn, Andrea Hamann, Dajana Parganlija |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Mitochondrion CLPX Lymphocyte Activation Mice 0302 clinical medicine T-Lymphocyte Subsets Gene Order Genetics (clinical) Growth Disorders Genetics Mice Knockout 0303 health sciences biology Proteolytic enzymes Mitochondrial medicine Energy and redox metabolism [IGMD 8] General Medicine Endopeptidase Clp Articles Phenotype Cell biology Mitochondria medicine.anatomical_structure Mitochondrial medicine [IGMD 8] Mitochondrial matrix Female Inflammation Mediators infertility Mitochondrial DNA Cell Respiration growth retardation Motor Activity DNA Mitochondrial mitochondrial peptidase 03 medical and health sciences Mitochondrial unfolded protein response medicine Animals Gonads Hearing Loss Molecular Biology 030304 developmental biology Spermatid Disease Models Animal Chaperone (protein) Infertility Mutation biology.protein 030217 neurology & neurosurgery Spleen Molecular Chaperones |
| Zdroj: | Human Molecular Genetics, 22, 24, pp. 4871-87 Europe PubMed Central Human Molecular Genetics, 22, 4871-87 Human Molecular Genetics Hum. Mol. Genet. 22, 4871-4887 (2013) |
| ISSN: | 0964-6906 |
| Popis: | Contains fulltext : 125623.pdf (Publisher’s version ) (Closed access) The caseinolytic peptidase P (CLPP) is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of CLPP null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction. |
| Databáze: | OpenAIRE |
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