Systems-Level Robustness and Fragility in the Cellular Organelle Network

A defining feature of the eukaryotic cell is its compartmentalization into organelles. While individual organelles have important functions on their own, they also make up a dynamic network whose interactions are responsible for vital cellular processes. A fundamental question in cellular biophysics is the degree to which the function of the cell is fragile or robust to perturbations to the organelle network. Here we aim to address the systems-level role organelle interactions play in regulating organelle composition and metabolic flows in the model system Saccharomyces cerevisiae. To dissect the organelle network, we have genetically broken interorganelle links formed by protein bridges called organelle contact sites. To assess the effects on organelle properties, we visualize a strain of budding yeast that expresses fluorescent labels for six organelles with hyperspectral confocal microscopy. This allows for simultaneous measurement of organelle size, number, and morphology at single cell resolution. Our data suggests that while metabolic hubs such as the ER, vacuoles, and peroxisomes are robust to network perturbations, mitochondria are a fragile node, with cells exhibiting divergent mitochondrial morphologies upon disruption of even non-mitochondrial network links. To examine the role robust organelles play in mitigating mitochondrial dysfunction, we present our initial characterization of the cell’s metabolic flexibility to disruptions in the organelle contact network.