Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress
| Autor: | Katarzyna Kisielewska, Malgorzata Urbanska, Agnieszka Chacinska, Ewa Liszewska, Lukasz Samluk, Jacek Jaworski, Karthik Mohanraj, Katarzyna Machnicka, Min-Ji Kim |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Eukaryotic Initiation Factor-2
P70-S6 Kinase 1 Antimycin A Biology Mechanistic Target of Rapamycin Complex 1 Models Biological 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cytosol Menadione Stress Physiological Humans Kinase activity Phosphorylation Molecular Biology PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Kinase Vitamin K 3 Cell Biology Articles Signaling Cell biology Mitochondria HEK293 Cells chemistry Protein Biosynthesis Reactive Oxygen Species 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 |
| Popis: | Previous studies demonstrated that cells inhibit protein synthesis as a compensatory mechanism for mitochondrial dysfunction. Protein synthesis can be attenuated by 1) the inhibition of mTOR kinase, which results in a decrease in the phosphorylation of S6K1 and 4E-BP1 proteins, and 2) an increase in the phosphorylation of eIF2α protein. The present study investigated both of these pathways under conditions of short-term acute and long-term mitochondrial stress. Short-term responses were triggered in mammalian cells by treatment with menadione, antimycin A, or CCCP. Long-term mitochondrial stress was induced by prolonged treatment with menadione or rotenone and expression of genetic alterations, such as knocking down the MIA40 oxidoreductase or knocking out NDUFA11 protein. Short-term menadione, antimycin A, or CCCP cell treatment led to the inhibition of protein synthesis, accompanied by a decrease in mTOR kinase activity, an increase in the phosphorylation of eIF2α (Ser51), and an increase in the level of ATF4 transcription factor. Conversely, long-term stress led to a decrease in eIF2α (Ser51) phosphorylation and ATF4 expression and to an increase in S6K1 (Thr389) phosphorylation. Thus, under long-term mitochondrial stress, cells trigger long-lasting adaptive responses for protection against excessive inhibition of protein synthesis. |
| Databáze: | OpenAIRE |
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