Fluctuations in organelle abundance can profoundly limit the precision of cell biological processes from secretion to metabolism. We modeled the dynamics of organelle biogenesis and predicted that organelle abundance fluctuations depend strongly on the specific mechanisms that increase or decrease the number of a given organelle. Our model exactly predicts the size of experimentally measured Golgi apparatus and vacuole abundance fluctuations, suggesting that cells tolerate the maximum level of variability generated by the Golgi and vacuole biogenesis pathways. We observe large increases in peroxisome abundance fluctuations when cells are transferred from glucose-rich to fatty acid-rich environments. These increased fluctuations are significantly diminished in mutants lacking peroxisome fission factors, leading us to infer that peroxisome biogenesis switches from de novo synthesis to primarily fission. Our work provides a general framework for exploring stochastic organelle biogenesis and using fluctuations to quantitatively unravel the biophysical pathways that control the abundance of subcellular structures.
Any cell that has a nucleus also contains various other organelles, such as the mitochondria that generate energy inside the cells. Like the nucleus, most of these organelles are enclosed within a membrane. Unlike the nucleus, however, there can be two or more copies of other types of organelles in a healthy cell.
How do the numbers of the different organelles in a cell change? The copy number for a given organelle can be increased in two ways: by the synthesis of new organelles, or the fission of an existing organelle to form two new organelles. Conversely, the number of organelles can also be decreased in two ways: an organelle can decay, or two organelles can fuse to form one new organelle. The steady state for a given organelle results from a balance of these creative and destructive processes.
Researchers have thought for some time that cells are able to count how many organelles of a given type they contain. It was also thought that cells have some control over this number, but it was not known how precisely cells could control the number of organelles they contained. It was also not known how this level of precision was influenced by the different processes responsible for making new organelles.
To address these issues, Mukherji and O'Shea have developed a stochastic model that treats the processes of organelle creation and destruction as if they were simple chemical reactions. A tool from statistical physics, known as the fluctuation-dissipation theorem, was then used to analyze this model and derive an equation that predicts how the fluctuations in organelle number depend on the rates of the processes that govern organelle number.
Mukherji and O'Shea used this model to make predictions about various organelles in the budding yeast S. cerevisiae. For two of these—vacuoles and the Golgi apparatus—the processes that lead to an increase or decrease in the number of organelles are well understood. In both cases the model accurately predicted the level of fluctuations measured in experiments. Moreover, Mukherji and O'Shea found that cells exhibited the maximum predicted level of fluctuations that could be generated by the processes that either increased or decreased the number of each organelle.
The model was also able to shed light on a long-running debate over the cellular origins of an organelle called the peroxisome. This organelle—which is involved in breaking down fatty acids and other compounds—has been studied much less than the Golgi apparatus and vacuoles, but there is compelling evidence that new peroxisomes are created by de novo synthesis and by the fission of existing peroxisomes.
Mukherji and O'Shea found that fluctuations in the number of peroxisomes suggest that the production of new peroxisomes is dominated by fission when the yeast cells are grown in a medium that is rich in oleic acid: peroxisomes are metabolically active and proliferate rapidly in such a medium. In a glucose-rich medium, on the other hand, most new peroxisomes are produced by de novo synthesis. The case of the peroxisome thus highlights the possibility of extending this mathematical framework to explain the creation and destruction of organelles and other subcellular structures in a range of organisms and environments.