Mass Spectrometry-Based Investigation of the Adaptive Response of Membrane Lipids to Glucose Stress in C. elegans

Xatse, Mark

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Mass Spectrometry-Based Investigation of the Adaptive Response of Membrane Lipids to Glucose Stress in C. elegans

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The unique composition of lipids that build biological membranes dramatically impacts an organism's cellular function and physiology. Environmental and dietary changes can influence the membrane lipid composition, leading to either perturbations in the membrane composition or adaptive changes to preserve membrane integrity and optimal cellular function. One of such typical stress is an elevated glucose diet, which is linked with alterations in lipid metabolism. This thesis employed targeted mass spectrometry, isotope labeling strategies, lifespan assays, and other biochemical methodologies to elucidate the membrane response mechanisms to glucose-induced stress in C. elegans. In doing so, we have uncovered novel adaptive responses to glucose stress in the nematodes critical for maintaining membrane homeostasis. We demonstrated that monomethyl branched-chain fatty acids are essential for the response to glucose stress by serving as precursors to glucosylceramide production. Using targeted lipidomics, we identified a specific glucosylceramide significantly upregulated with glucose stress in wild-type animals. Notably, compromising the production of glucosylceramides leads to premature death in glucose-fed animals. We posit that glucosylceramides mediate signaling events, potentially through the TORC complex. Furthermore, we investigated the underlying stress caused by glucose and uncovered the critical need for active polyunsaturated fatty acid (PUFA) synthesis under glucose-induced stress conditions. This is attributed to the damage of PUFAs caused by glucose-induced oxidative stress, leading to the accumulation of oxidized lipids. Notably, the accumulation of oxidized lipids is selectively higher in phosphatidylethanolamine (PE), suggesting that oxidative stress induced by glucose occurs in specific localizations where PE is particularly enriched. This dissertation underscores the intricate interplay between glucose stress, membrane lipid dynamics, and physiological outcomes, providing a mechanistic understanding of metabolic adaptability in response to nutritional stress.

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