Increased S6K1 phosphorylation protects against early steps of Tau aggregation under long-term mitochondrial stress

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. * 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