The design principles of the eukaryotic cell: uncovering the coordination of systems-level organelle dynamics, metabolism and growth

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Project Summary Perhaps the defining feature of the eukaryotic cell is its organization into biochemically distinct compartments known as organelles. While the biochemical functions of individual organelles are often well known, how cells regulate the copy numbers, sizes, and subcellular positions of its diverse organelles in a coordinated fashion and how organelles interact to produce integrated physiological outputs remain one of the grand challenges in cell biology. The goal of my research program is to discover the quantitative principles governing how cells regulate systems-level organelle dynamics to coordinate metabolism, growth, and proliferation. To achieve this goal, my research strategy will proceed along two directions. In the first direction, I will quantitatively determine how cells coordinate systems-level organelle dynamics with cellular growth demands. Specifically, I will quantify and build a mathematical model of the relationship between cellular organelle composition and cell growth. The model will be calibrated from data obtained by simultaneously visualizing all major metabolic organelles using our machine learning-based hyperspectral imaging platform, exerting chemical biological control over cell growth and proliferation rates, and genetically perturbing key organelle biogenesis, organization, and interaction factors. In the second direction, I will determine how cells coordinate systems-level organelle dynamics and gene expression to control metabolism during growth and proliferation. I will categorize single cells according to their organelle content and systematically measure the temporal correlations in their expression of genes whose products execute organelle-specific functions. I will concomitantly measure the metabolomic profile of these cells sorted by organelle content. I will then combine these measurements to develop a mathematical model that quantitatively captures the connection between gene expression and metabolism as mediated by the cell's organelle makeup. I will subsequently test predictions of this model by systematically tuning organelle interaction strengths by modulating the expression of organelle biogenesis factors and organelle contact sites. Successful investigations along these two directions will yield mechanistic insight into how to untangle the complex interdependencies between organelle dynamics, metabolism, and cell growth and proliferation. A systems- level understanding of how organelle composition and interactions coordinate metabolism to control cellular growth and development will lay a rigorous foundation into future investigations into how the cell actively shapes its organelle composition to match biochemical supply with physiological demand through, how this plasticity is leveraged in health by multicellular organisms to provide the metabolic flexibility needed to develop its myriad cell types, but also in disease by allowing for multiple routes to metabolic pathologies in cancer, diabetes, and aging.