Grant: Alliance Grants

Living cells carry out many functions, enabled by the activity of molecular machines known as proteins. Protein populations vary between different cell regions, enabling specialized function of these regions. Proteins are encoded by DNA, which is transcribed to messenger RNA (mRNA) that is translated into proteins by ribosomes. Most mitochondrial proteins must be imported, and mRNA can become tethered to a specific mitochondria as a protein can begin mitochondrial import while it is still being made by the ribosome. While mitochondria are often depicted as bean-shaped objects, in many cells they typically form extended tubular networks that frequently dynamically rearrange their structure. Mitochondrial fragmentation into many small mitochondria is associated with diseases, with onset of mitochondrial dysfunction shown to occur after a sustained period of fragmentation. However, it is unknown how mitochondrial fragmentation leads to dysfunction. Recent work shows that the distribution of proteins between mitochondria becomes much more uneven for small fragmented mitochondria when proteins are delivered by mRNA tethered to specific mitochondria, providing a connection between mitochondrial fragmentation and function. This project will develop mathematical modeling to understand and explain how mitochondrial protein delivery characteristics combine with mitochondrial dynamics (which determine the extent of mitochondrial fragmentation) to control how uneven protein levels are between different mitochondria. Mitochondrial dysfunction is tied to neurodegenerative and metabolic diseases, as well as the aging process, and the results of this work may point towards therapeutic targets.