Deciphering the role of eIF5A in mitochondrial function

Project Summary/Abstract The eukaryotic initiation factor 5A (eIF5A) is a conserved translation factor that is important for the resolution of certain ribosome stalls. eIF5A has been found to be integral for mitochondrial function from yeast to mammalian cells. Despite its recognized importance across species, the precise molecular mechanism by which eIF5A influences mitochondria is not fully understood. This gap in knowledge is especially pertinent given the established links between mitochondrial dysfunction and a range of diseases, including neurodegenerative disorders and cancer. The central objective of this project is to elucidate the mechanisms through which eIF5A depletion affects mitochondrial function, hypothesizing that such depletion leads to ribosome stalling on mitoproteins during co-translational import. This stalling is thought to trigger a mitochondrial import stress response, influencing the translation of various mitochondrial proteins and, consequently, the overall cellular health and function. By integrating gene expression reporters with advanced methodologies such as fluorescent microscopy, proteomics, CRISPR library screening, and Cryo- Electron Tomography, this research promises to offer comprehensive insights into eIF5A's role in mitochondrial health and dysfunction. The outcomes are expected to not only deepen our understanding of fundamental mitochondrial biology but also highlight potential therapeutic avenues for tackling diseases associated with mitochondrial dysfunction.