Trade-off between organelle number and size fluctuations suggest that a limiting pool of building blocks biophysically constrains organelle biogenesis

One of the hallmarks of the eukaryotic cell is its organization into distinct spatial compartments known as organelles, that mediate processes critical to cellular function. While the regulation of the abundance and size of organelles plays a profound role in the function and health of a cell, very little is known about the biophysical underpinnings of organelle size regulation. To achieve mechanistic insight into organelle size regulation, we examined three general limits of a comprehensive mathematical model of organelle growth, in which growth either occurs at a constant rate, is regulated by a negative feedback process, or is constrained by a limiting-pool of building blocks. Experimentally, we tested our model on lipid droplets and peroxisomes, two key organelles in cellular lipid metabolism, using quantitative confocal fluorescent microscopy to obtain joint probability distributions of organelle number and size at a single cell resolution. Statistical analyses of our models over a large parameter space and comparison to mutant strains of yeast are consistent with a limiting-pool of organelle building blocks biophysically constraining the size of lipid droplets and peroxisomes.