Cellular remodeling in response to nutrient exhaustion : From membrane contact sites to autophagy

Abstract: Adaptation to fluctuating environments is critical for cellular fitness and survival. Cells need to sense changes in their surroundings and quickly adjust cellular homeostasis and metabolism accordingly. Diverse sensing and signaling pathways govern the cellular responses to extracellular cues, enabling for instance adaptation to changes in nutrient availability. Eukaryotic cells have evolved complex regulatory networks to deal with variable nutrient supply, and most of these evolutionary conserved nutrient signaling pathways are intimately linked to aging and age-associated diseases. Despite significant advances, the adaptation to environmental changes through nutrient signaling pathways and the impact of these pathways on a cell’s lifespan remain incompletely understood. This thesis focuses on the molecular mechanisms by which nutrient depletion affects cellular remodeling and lifespan of the budding yeast Saccharomyces cerevisiae. In paper I, we elucidate the impact of nutritional regimes on cellular survival during aging, with a particular focus on phosphate restriction. We show that phosphate restriction results in an activation of autophagy, the main cellular bulk degradation process, and a prominent extension of lifespan. Our results indicate that longevity induced by phosphate restriction relies on the sequential and coordinated function of autophagy and the multivesicular body pathway, a catabolic process critical for the degradation of plasma membrane components. In addition, we find the nutrient-responsive kinase Pho85 to be essential for autophagy induction and cellular fitness upon phosphate restriction. In paper II, we illustrate how nutrition limitation affects interorganellar communication as well as lipid droplet biogenesis, subcellular organization and utilization. We demonstrate that phosphate depletion induces the remodeling and expansion of the contacts between the perinuclear ER and the vacuole, the so-called nucleus-vacuole junctions. Moreover, we show that the biosynthesis of sterol esters, which are stored in lipid droplets upon nutrient depletion, is essential for survival upon phosphate but not glucose exhaustion. In paper III, we identify Snd3 as novel component of the nucleus-vacuole junctions, critical for membrane contact site formation and dynamic remodeling upon glucose exhaustion. Additionally, we show that the regulatory function of Snd3 is governed by central glucose signaling pathways. Taken together, our studies advance our understanding of how nutritional regimes and signaling pathways impact on cellular remodeling and survival during aging.