Abstract
Many studies demonstrated the influence of mitochondrial stress on cytosolic signaling pathways. Here, we found that in cells upon long-term mitochondrial stress, phosphorylation of S6K1 protein, which is the mTOR pathway component, was increased, like in brains of Alzheimer’s disease (AD) patients. We checked if increased S6K1 phosphorylation was involved in Tau protein aggregation, which is one of AD hallmarks. HEK239T NDUFA11-deficient cells treatment with the mTOR inhibitor, INK128, or with S6K1 inhibitor, PF-4708671, caused the elevation of Tau aggregation. In contrast, stable overactivation of the mTOR pathway caused a further increase of S6K1 phosphorylation and reduced Tau oligomerization in HEK239T NDUFA11-deficient cells. Thus, we conclude that the increase in S6K1 phosphorylation is protective against Tau aggregation under mitochondrial stress.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- AD
- Alzheimer’s disease
- AMPK
- adenosine monophosphate-activated protein kinase
- BiFC
- bimolecular fluorescence complementation
- DEPTOR
- DEP domain-containing mTOR-interacting protein
- DMEM
- Dulbecco’s Modified Eagle Medium
- DTT
- dithiothreitol
- EDTA
- ethylenediaminetetraacetic acid
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- mLST8
- mammalian lethal with SEC thirteen 8
- mTOR
- mechanistic target of rapamycin
- mTORC1
- mTOR complex 1
- NDUFA11
- NADH:ubiquinone oxidoreductase subunit A11
- PBS
- phosphate-buffered saline
- PMSF
- phenylmethylsulfonyl fluoride
- PRAS40
- proline-rich AKT substrate of 40 kDa
- Raptor
- regulatory-associated protein of mTOR
- S6K1
- ribosomal protein S6 kinase 1
- SDS-PAGE
- sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- SEM
- standard error of the mean
- TSC2
- tuberous sclerosis complex 2