Lipidic drivers of organelle function and dysregulation

PROJECT SUMMARY Lipids represent a diverse class of biomolecules that are the building blocks of cell membranes. In recent years, alterations in lipid composition have been identified as hallmarks of numerous diseases, ranging from type 2 diabetes to neurodegenerative disorders. However, understanding the functional roles of bulk membrane lipids has long been a challenge, in part due to the difficulties of manipulating and imaging them in cells. Our laboratory applies genetic and chemical tools to study lipid function and develop biophysical models for membrane- associated cellular processes. The proposed research program will carry out this approach to identify how two disease-associated lipid perturbations alter the behavior of cellular compartments. In the first thrust, we will use effects of saturated phospholipids on membrane viscosity to uncover how structure and dynamics control respiratory metabolism. Specifically, we will engineer inner mitochondrial membrane composition in both yeast and mammalian cell lines and use this perturbation to dissect the contributions of diffusion and supramolecular assembly to the electron transport chain. This effort will uncover the function of conserved features of mammalian mitochondria, such as respiratory supercomplexes, and test how increases in saturated lipids caused by metabolic disorders could directly contribute to mitochondrial dysfunction. In the second thrust, we will use a genetic system to interrogate the function of 1-deoxysphinglipids, non-canonical products of serine- palmitoyltransferase that have been associated with several genetic and metabolic disorders. We will focus on how synthesis of 1-deoxysphinglipids dysregulates the endomembrane system in retinal pigment epithelium cells, which have been linked to adult-onset blindness caused by 1-deoxysphinglipid accumulation. Development of new imaging approaches will broaden the impact of this thrust to the emerging biomedical roles for these enigmatic lipids. If executed, the research program will thus generate models for two sets of lipids molecules and their cellular points of action in both healthy and diseased cells. Our long-term goal is to understand how changes in lipid composition across organelles, cells, and tissues arise and function, and use this knowledge to uncover the molecular mechanisms underlying membrane biology.