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

• Final Report Year: 2024

Final Report Abstract

Aging is a natural phenomenon characterized by a progressive decline despite complex pathways of maintenance and repair. The loss of proteostasis in aging results in the inability of proteins to achieve and maintain their native three-dimensional structure and perform their functions efficiently. To counteract this, cells have evolved mechanisms to promote the removal of damaged proteins through degradation and nucleation and growth of protein aggregates. The functions of protein refolding, targeting to degradation and aggregate nucleation are all performed by molecular chaperones. Using budding yeast S. cerevisiae as a model system, we investigated how changes in proteostasis affect protein condensation, modulate metabolic pathway activity and extend lifespan. Our study reveals a previously unknown role of Hsp42 in SG dynamics during the response to glucose starvation. We found that SG formation and dissolution are stepwise processes in wild- type cells, involving fusion and fission events, respectively. Notably, this phenotype is attributed to the N-terminal domain of Hsp42. Moreover, our results show that the absence of Hsp42 leads to an extension of yeast replicative lifespan (RLS) that requires a switch to respiratory metabolism, despite the abundance of glucose, accompanied by a decline in glucose uptake. These results illustrate dynamic communication between proteostasis, metabolism and lifespan driven by Hsp42 deficiency.

Publications

• ATP hydrolysis by yeast Hsp104 determines protein aggregate dissolution and size in vivo. Nature Communications, 11(1).
  Sathyanarayanan, Udhayabhaskar; Musa, Marina; Bou, Dib Peter; Raimundo, Nuno; Milosevic, Ira & Krisko, Anita
  
• CORE at the boundary of stress resistance and longevity. The International Journal of Biochemistry & Cell Biology, 151, 106277.
  Lippi, Alice & Krisko, Anita
  
• Lack of peroxisomal catalase affects heat shock response in Caenorhabditis elegans. Life Science Alliance, 6(1), e202201737.
  Musa, Marina; Dionisio, Pedro A.; Casqueiro, Ricardo; Milosevic, Ira; Raimundo, Nuno & Krisko, Anita
  
• Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity. Molecular Cell, 83(18), 3360-3376.e11.
  Paukštytė, Jurgita; López, Cabezas Rosa María; Feng, Yuehan; Tong, Kai; Schnyder, Daniela; Elomaa, Ellinoora; Gregorova, Pavlina; Doudin, Matteo; Särkkä, Meeri; Sarameri, Jesse; Lippi, Alice; Vihinen, Helena; Juutila, Juhana; Nieminen, Anni; Törönen, Petri; Holm, Liisa; Jokitalo, Eija; Krisko, Anita; Huiskonen, Juha ... & Saarikangas, Juha
  
• Protein aggregation: A detrimental symptom or an adaptation mechanism?. Journal of Neurochemistry, 168(8), 1426-1441.
  Lippi, Alice & Krisko, Anita