Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol
| Autor: | Marta Koblowska, Andrzej Dziembowski, Elzbieta Januszewicz, Sebastian Wiese, Malgorzata E. Sztolsztener, Lidia Wrobel, Aksana Varabyova, Agnieszka Chacinska, Silke Oeljeklaus, Piotr Chroscicki, Ulrike Topf, Seweryn Mroczek, Piotr Bragoszewski, Bettina Warscheid, Maciej Lirski |
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| Rok vydání: | 2015 |
| Předmět: |
0303 health sciences
Multidisciplinary biology medicine.disease_cause Mitochondrial carrier Cell biology 03 medical and health sciences Mitochondrial membrane transport protein 0302 clinical medicine mitochondrial fusion Mitochondrial biogenesis Biochemistry Protein targeting Translocase of the inner membrane medicine biology.protein DNAJA3 ATP–ADP translocase 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Nature |
| ISSN: | 0028-0836 |
| DOI: | 10.1038/nature14951 |
| Popis: | Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction. |
| Databáze: | OpenAIRE |
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