Proteostasis-metabolism interplay in safeguarding cellular longevity

• Applicant: Dr. Anita Krisko
• Subject Area: Cell Biology ; Biochemistry ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 443310721

Aging is a natural phenomenon that occurs despite complex pathways of maintenance and repair. As chronological age of an organism increases, a number of errors accumulate at different levels of biological organization. The tendency of errors to accumulate and cause downstream problems in maintenance of cellular homeostasis is met by numerous protection and repair mechanisms. Our project seeks to understand the interplay between the protein homeostasis and the cellular metabolic activity, in particular the role it has in decisions regarding cell fate. We focus on elucidation of cellular and molecular mechanisms underlying the proteostasis-metabolism crosstalk across cellular compartments. We aim to obtain an integrated picture of the effects that the quality of protein folding environment is able to yield on cellular metabolism, thus contributing to understanding of the implications of this multifaceted network in aging and disease. Another intriguing question that we are addressing in this research proposal is related to the role of protein aggregation in aging. Extensive research has so far not given an answer whether protein aggregation is beneficial for the cell or if it represents a detrimental event threatening cell viability. We aim to tackle it using novel methodologies combined with lifespan analyses. In addition, we are proposing to test the hypothesis that proteostasis failure and protein aggregation during aging are a consequence of an altered metabolic state of an old cell, rather than an independent event. This would open possibilities for the rescue of age-related proteostasis failure and perhaps also extend cellular lifespan. The main tenet of this project is that the changes in cellular phenotypes are concerted, thus accentuating the importance of integration of signaling pathways so far studied separately. Such approach is largely missing from the on-going research, and it represents the main strength of the described project. We will use budding yeast, Saccharomyces cerevisiae, as our primary model organism, in a system-wide approach unifying genomics, proteomics and live cell imaging methodologies. While high-risk in its nature due to the enormous complexity of the interactions between key players in this crosstalk, and the ambitious research methodology, the proposal has a potential to strongly influence main paradigms of cell biology by identifying and describing a novel cellular communication pathways. The proposed DFG funding is essential for the success of this ambitious and well-timed project, which will consolidate my position as a senior scientist in research on cellular homeostasis and aging.

• DFG Programme: Research Grants