NSF-DFG: Investigating Ribosome Tethering to Mitochondria in Dormant Yeast Cells

• Applicant: Dr. Simone Mattei
• Subject Area: Structural Biology ; Biochemistry ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560460101

We aim to establish a state-of-the-art scientific program to understand the molecular and cellular mechanisms driving cell dormancy and survival across various environmental conditions. Dormancy is a quiescent cellular state present in all forms of life, including plants, bacteria, and fungi. Notably, dormant cells cease dividing and exhibit the remarkable ability to conserve energy and resources until favorable environmental conditions are restored. Recently, we discovered a novel adaptive mechanism in dormant fission yeast cells, Schizosaccharomyces pombe, where cytoplasmic ribosomes hibernate on mitochondria. We found this adaptive response to be important for cell survival under stress conditions. Our discovery of stable ribosome sequestration on mitochondria during hibernation represents a significant conceptual advancement with respect to the previously known transient interactions of translating ribosomes during mitochondrial protein import. This response, which leads to suppressed protein synthesis, forms the basis of our investigation. Our approach uniquely leverages nutrient cues, a condition commonly encountered by yeast in their natural environment, to modulate ribosomal interactions with mitochondria and to investigate how nutrients-induced stress responses promote cell survival. The method-based innovation of our discovery-driven approach lies in the integration of advanced cellular, molecular, and structural biology techniques to elucidate the molecular mechanisms underpinning cellular dormancy and survival. By combining in situ cryo-electron tomography (cryo-ET), high-resolution cryo-electron microscopy (cryo-EM), biochemistry, and yeast genetics we will be able to investigate the landscape of cellular adaptations at the molecular level within the cellular context, surpassing previous technical limitations.The proposed research will develop an integrative platform combining cellular and structural biology with yeast genetics and biochemistry to understand the molecular mechanism of ribosome hibernation on mitochondria and how it promotes cell survival during dormancy. The proposal outlines three specific aims to be studied over three years in a collaborative effort between the Jomaa team at the University of Virginia, USA, and the Mattei team at EMBL, Germany:1) We will determine the mitochondrial receptor involved in ribosome tethering during glucose depletion.2) We will investigate how RACK1, the ribosomal protein responsible for mitochondrial tethering, regulates cell survival and mitochondrial function during nutrients-induced cellular stress.3) Since dormancy is a reversible process, we will reveal the structural basis of protein synthesis-restart and ribosome release from mitochondria once nutrient cues are alleviated.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Ahmad Jomaa