Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders
| Autor: | Charlotta Funaya, Marc Blondel, Raeka S. Aiyar, Lars M. Steinmetz, Elodie Couplan, Claude Antony, Florence Courtin, Emilie S. Fritsch, Roza Kucharczyk, Karina von der Malsburg, Martin van der Laan, Justine Evrard, Sundari Suresh, Robert P. St.Onge, Flavie Soubigou, Jean-Paul di Rago, Cécile Voisset, Stéphane Duvezin-Caubet, Maria Bohnert, Julien Gagneur |
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| Rok vydání: | 2014 |
| Předmět: |
Antifungal Agents
Mitochondrial Diseases Saccharomyces cerevisiae Proteins Databases Pharmaceutical Pyridines General Physics and Astronomy Saccharomyces cerevisiae Oxidative phosphorylation Mitochondrion medicine.disease_cause Mitochondrial Membrane Transport Proteins Mitochondrial Proton-Translocating ATPases Article Oxidative Phosphorylation General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mitochondrial membrane transport protein 0302 clinical medicine Mitochondrial Precursor Protein Import Complex Proteins Protein targeting medicine Humans Molecular Targeted Therapy 030304 developmental biology Cell Nucleus 0303 health sciences Multidisciplinary biology ATP synthase Drug Repositioning Membrane Transport Proteins Nuclear Proteins Thiones General Chemistry Mitochondria 3. Good health Cell biology Protein Transport Gene Expression Regulation Mitochondrial biogenesis Biochemistry mitochondrial fusion Mutation biology.protein 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms6585 |
| Popis: | Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases. Effective treatment options for mitochondrial diseases are scarce. Here, Aiyar et al. identify the TIM23 mitochondrial protein sorting machinery as a potential intervention point for mitochondrial ATP synthase disorders. |
| Databáze: | OpenAIRE |
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