Krisko, A. | Search bioRxiv

bioRxiv2023

Global analysis of aging-related protein structural changes uncovers enzyme polymerization-based control of longevity

Aging is associated with progressive phenotypic changes over time. Virtually all cellular phenotypes are produced by proteins and structural alterations in proteins can lead to age-related diseases. Nonetheless, comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contribution to age-related phenotypes is lacking. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry. The results, compiled in online ProtAge-catalog, unravelled age-related functional changes in regulators of translation, protein folding and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction and led to life span extension. Altogether, this comprehensive map of protein structural changes enables identifying novel mechanisms of age-related phenotypes and offers opportunities for their reversal.

cell biology↗

bioRxiv2021

Functional peroxisomes are required for heat shock-induced hormesis in Caenorhabditis elegans

Exact mechanisms of heat shock induced lifespan extension, while documented across species, are still not well understood. Here we put forth evidence that fully functional peroxisomes are required for the activation of the canonical heat shock response and heat-induced hormesis in C. elegans. While during heat shock the HSP-70 chaperone is strongly upregulated in the wild-type (WT) as well as in the absence of peroxisomal catalase ({Delta}ctl-2 mutant), the small heat shock proteins display modestly increased expression in the mutant. Nuclear localization of HSF-1 is reduced in the{Delta} ctl-2 mutant. In addition, heat-induced lifespan extension, observed in the WT, is absent in the{Delta} ctl-2 mutant. Activation of the antioxidant response, the pentose phosphate pathway and increased triglyceride content are the most prominent changes observed during heat shock in the WT worm, but not in the{Delta} ctl-2 mutant. Involvement of peroxisomes in the cell-wide response to transient heat shock reported here gives new insight into the role of organelle communication in the organisms stress response.

cell biology↗