Mitochondrial stress response triggered by defects in protein synthesis quality control
| Autor: | Paula Marttinen, Brendan J. Battersby, Eija Jokitalo, Cecilia Mancini, Tuula A. Nyman, Sara Seneca, Fumi Suomi, Anu Suomalainen, Helena Vihinen, Taina Turunen, Christopher B. Jackson, Uwe Richter, Anne Lombès, Kah Ying Ng, Alfredo Brusco, James B. Stewart, Marita A Isokallio, Robert W. Taylor |
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| Přispěvatelé: | Institute of Biotechnology, University of Helsinki, Research Programs Unit, Anu Wartiovaara / Principal Investigator, STEMM - Stem Cells and Metabolism Research Program, HUSLAB, Department of Neurosciences, University Management, Electron Microscopy, Clinical sciences, Medical Genetics, Reproduction and Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
RNA
Messenger/genetics chloramphenicol protein synthesis Health Toxicology and Mutagenesis Plant Science Mitochondrion OPA1 GTP Phosphohydrolases Mitochondrial Ribosomes Mitochondrial Proteins/biosynthesis 0302 clinical medicine ATP-Dependent Proteases Mitochondrial ribosome Protein biosynthesis Genetics(clinical) RNA Small Interfering Inner mitochondrial membrane SPASTIC PARAPLEGIA Research Articles Fibroblasts/metabolism RNA Small Interfering/genetics 0303 health sciences Ecology Paraplegin Chemistry M-AAA PROTEASE Metalloendopeptidases Mitochondrial Membranes/metabolism Cell biology READ ALIGNMENT mitochondria Phenotype ATP-Dependent Proteases/genetics Mitochondrial matrix Gene Knockdown Techniques Mitochondrial Membranes TURNOVER Research Article Metalloendopeptidases/metabolism reproductive medicine mice COMPUTATIONAL PLATFORM Oxidative phosphorylation ATAXIA Transfection mitochondria AFG3L2 protein synthesis inner mitochondrial membrane chloramphenicol Biochemistry Genetics and Molecular Biology (miscellaneous) ATPases Associated with Diverse Cellular Activities/genetics Mitochondrial Proteins 03 medical and health sciences Mitochondria/metabolism DNA DELETIONS Animals Humans RNA Messenger AFG3L2 inner mitochondrial membrane 030304 developmental biology Biochemistry Genetics and Molecular Biology(all) MUTATIONS Mitochondrial Ribosomes/metabolism Fibroblasts HEK293 Cells Membrane protein Protein Biosynthesis ATPases Associated with Diverse Cellular Activities 1182 Biochemistry cell and molecular biology 3111 Biomedicine GTP Phosphohydrolases/metabolism mutation MEMBRANE 030217 neurology & neurosurgery |
| Zdroj: | Life Sci Alliance Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | Quality control defects of mitochondrial nascent chain synthesis trigger a sequential stress response characterized by OMA1 activation and ribosome decay, determining mitochondrial form and function. Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis. |
| Databáze: | OpenAIRE |
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