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

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 Alzheimers 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.