MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure
| Autor: | Georg Auburger, Zoe H. Davis, Ishaq Tantray, Michael Snyder, Xiaolin Bi, Yu Li, Zhihao Wu, Songjie Chen, Suzana Gispert, Junghyun Lim, Bingwei Lu, Cole S. Sitron, Jason Dong, Onn Brandman |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Mitochondrial Diseases
RNA Mitochondrial Translational termination Protein subunit Biology Ribosome Article Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine medicine Animals Drosophila Proteins Humans Proteostasis Deficiencies Molecular Biology 030304 developmental biology 0303 health sciences Messenger RNA Neurodegeneration Cell Biology medicine.disease Stop codon Mitochondria Cell biology Cytosol Drosophila melanogaster Proteostasis Codon Terminator 030217 neurology & neurosurgery Homeostasis HeLa Cells |
| Zdroj: | Mol Cell |
| DOI: | 10.1101/554634 |
| Popis: | SUMMARYMitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here we describe a phenomenon termed MISTERMINATE (mitochondrial stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs including complex-I 30kD subunit (C-I30) mRNA, occurring on mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C-terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally-extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson’s disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE. |
| Databáze: | OpenAIRE |
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