Samluk, L. | Search bioRxiv

bioRxiv2022

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 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.

cell biology↗

bioRxiv2021

Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimers and Parkinsons diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

cell biology↗