المؤلفون: Kat Folz-Donahue, Ilian Atanassov, James B. Stewart, Sara Albarran-Gutierrez, Xinping Li, Nils-Göran Larsson, Min Jiang, Timo E.S. Kauppila, Nina A. Bonekamp, Elisa Motori

المصدر: Cell Metab

مصطلحات موضوعية: Male, 0301 basic medicine, Mitochondrial DNA, DNA Copy Number Variations, Physiology, Mice, Transgenic, Spermatocyte, Biology, Mitochondrion, medicine.disease_cause, DNA, Mitochondrial, Male infertility, Mice, 03 medical and health sciences, Spermatocytes, Testis, medicine, Animals, Molecular Biology, Infertility, Male, Genetics, Mutation, Cell Biology, TFAM, medicine.disease, Molecular biology, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Spermatogenesis

الوصف: Mutations of mtDNA cause mitochondrial diseases and are implicated in age-associated diseases and aging. Pathogenic mtDNA mutations are often present in a fraction of all mtDNA copies, and it has been widely debated whether the proportion of mutant genomes or the absolute number of wild-type molecules determines if oxidative phosphorylation (OXPHOS) will be impaired. Here, we have studied the male infertility phenotype of mtDNA mutator mice and demonstrate that decreasing mtDNA copy number worsens mitochondrial aberrations of spermatocytes and spermatids in testes, whereas an increase in mtDNA copy number rescues the fertility phenotype and normalizes testes morphology as well as spermatocyte proteome changes. The restoration of testes function occurs in spite of unaltered total mtDNA mutation load. We thus demonstrate that increased copy number of mtDNA can efficiently ameliorate a severe disease phenotype caused by mtDNA mutations, which has important implications for developing future strategies for treatment of mitochondrial dysfunction.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d00a289efde3d84fbbd0a89a5675223bTest
https://doi.org/10.1016/j.cmet.2017.07.003Test

المؤلفون: Frank Schnorrer, Pontus Klein, Elisa Motori, Konstanze F. Winklhofer, Cornelia Schönbauer, Rüdiger Klein, Anne Kathrin Müller-Rischart

المصدر: The EMBO journal 33(4), 341-355 (2014). doi:10.1002/embj.201284290
The EMBO Journal
EMBO JOURNAL

مصطلحات موضوعية: endocrine system diseases, pharmacology [Glial Cell Line-Derived Neurotrophic Factor], Parkinson's disease, Dopamine, Mutant, prevention & control [Muscular Atrophy], Apoptosis, park protein, Drosophila, Mitochondrion, Parkin, PINK1 protein, Drosophila, Neuroblastoma, Adenosine Triphosphate, 0302 clinical medicine, genetics [Drosophila Proteins], physiology [Electron Transport Complex I], Mitophagy, Glial cell line-derived neurotrophic factor, pathology [Neuroblastoma], Drosophila Proteins, metabolism [Dopamine], Neurons, Genetics, ultrastructure [Neurons], genetics [Ubiquitin-Protein Ligases], genetics [Drosophila melanogaster], 0303 health sciences, General Neuroscience, Neurodegeneration, genetics [Protein Kinases], neurodegeneration, Pupa, Parkinson Disease, deficiency [Protein Kinases], genetics [Proto-Oncogene Proteins c-ret], Articles, Muscle degeneration, Protein-Serine-Threonine Kinases, OXPHOS, Mitochondrial morphology, Cell biology, ultrastructure [Mitochondria, Muscle], Muscular Atrophy, Drosophila melanogaster, Phenotype, Proto-Oncogene Proteins c-ret, Drosophila, Corrigendum, PTEN-induced putative kinase, Drosophila Protein, Signal Transduction, Ret protein, Drosophila, neurotrophic factors, Ubiquitin-Protein Ligases, PINK1, Protein Serine-Threonine Kinases, deficiency [Ubiquitin-Protein Ligases], Biology, genetics [Protein-Serine-Threonine Kinases], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Oxygen Consumption, ddc:570, Cell Line, Tumor, physiology [Signal Transduction], medicine, Autophagy, Animals, Humans, Glial Cell Line-Derived Neurotrophic Factor, Molecular Biology, 030304 developmental biology, physiology [Protein-Serine-Threonine Kinases], Electron Transport Complex I, General Immunology and Microbiology, deficiency [Drosophila Proteins], physiology [Drosophila Proteins], medicine.disease, Mitochondria, Muscle, deficiency [Protein-Serine-Threonine Kinases], Disease Models, Animal, physiology [Proto-Oncogene Proteins c-ret], metabolism [Adenosine Triphosphate], biology.protein, Genes, Lethal, growth & development [Drosophila melanogaster], Protein Kinases, 030217 neurology & neurosurgery

الوصف: Synopsis image Glial cell line derived neurotrophic factor (GDNF) improves survival in toxin-models of Parkinson's disease and is currently undergoing clinical development, however the protective mechanism is elusive. This study provides evidence that the GDNF receptor Ret rescues defects of a genetic Parkinson model and proposes a new mechanism-of-action. Active Ret overexpression rescues muscle degeneration and mitochondrial morphology in muscles and dopamine neurons in Pink1 mutant Drosophila. In human neuroblastoma cells, GDNF treatment rescues mitochondrial fragmentation caused by Pink1 knockdown. Ret signaling improves mitochondrial respiration and activity of complex I, providing a potential novel mechanism for the protective effect of GDNF/Ret. Abstract Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN)(2B)) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN)(2B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e0ad2f28b140c59168af44036cb9f31cTest
https://doi.org/10.1002/embj.201470060Test