Kaper, Delaney2025-05-052025-05-052025-05-05978-91-8115-256-2 (Print)978-91-8115-257-9 (PDF)https://hdl.handle.net/2077/85850Since the 1930s, scientists have known that certain unsaturated fatty acids are essential in the human diet and act as precursors for further fatty acid synthesis. Unlike humans, the nematode C. elegans can de novo synthesize omega-3 and omega-6 polyunsaturated fatty acids, making it a useful species for studying fatty acid function. Fatty acids form the tails of phospholipids, the main component of cellular membranes, and modulating the identity of these tail fatty acids has important implications for membrane homeostasis. Saturated fatty acids have membrane rigidifying effects, while unsaturated fatty acids fluidize membranes; thus, a proper balance between the two is crucial for several membrane properties. One way by which cells achieve membrane homeostasis is through the PAQR-2 membrane fluidity regulator that responds to membrane rigidification by increasing fatty acid desaturation and incorporation of unsaturated fatty acids into phospholipids. In the first part of this thesis, the effect of excessively rigid and excessively fluid membranes on several cellular and physiological traits were studied in C. elegans and revealed that deviation from optimal membrane composition in either direction is deleterious. Next, we further characterized the molecular basis of PAQR-2 activity, revealing that PAQR-2 recruits a complex containing enzymes important for fatty acid elongation and for channeling of unsaturated fatty acids into phospholipids. In the final part of this thesis, a forward genetics screen led to the discovery that the HIF-1 pathway can potentiate desaturase activity in a C. elegans mutant that is almost wholly devoid of polyunsaturated fatty acids. We conclude that the PAQR-2 and HIF-1 pathways are regulators of unsaturated fatty acid homeostasis essential for the physiological health of C. elegans.engPAQR-2HIF-1FAT-2fatty acid synthesismembrane homeostasisunsaturated fatty acidC. elegansText