Understanding how sphingolipid metabolism regulates mitochondrial maintenance in aging cells

Project Summary: Aging is the prime risk factor for many human diseases including diabetes, cardiovascular disorders, neurological dysfunctions, and cancers. One of the pillars of aging is mitochondrial function, which declines as organisms and cells age. However, the mechanisms contributing to mitochondrial dysfunction in aging cells are not completely understood. Sphingolipid depletion increases longevity in multiple aging models, but the mechanistic basis is not well understood. My preliminary data reveals that decreasing sphingolipid levels preserves mitochondrial morphology and function in aging cells. This raises important questions about the relationship between sphingolipid metabolism and mitochondrial maintenance, particularly in the context of aging or stress. To address these questions, I propose two research aims that examine the relationship between sphingolipid metabolism and mitochondrial biology using two different aging models. The first aim seeks to determine the mechanism of mitochondrial swelling in an aging model of the yeast Saccharomyces cerevisiae. This aim will examine the hypothesis that swelling is caused by accumulation of sphingolipids in aging mitochondrial membranes. Additionally, this aim will map sphingolipid trafficking itineraries in the cell, testing the hypothesis that sphingolipid transport across organelle contact sites contributes to mitochondrial swelling and dysfunction aging cells. This research will contribute new insights at the interface of lipid metabolism and inter-organelle communication. My second research aim will investigate the relationship between sphingolipid metabolism and mitochondrial stress responses using the C. elegans aging model. My preliminary data indicates that sphingolipid depletion in C. elegans suppresses mitochondrial stress responses, and in this aim I will address the mechanistic basis of this suppression. Additionally, I will develop new tools to achieve inducible, tissue-specific sphingolipid depletion in C. elegans. Using these new tools, I will determine how tissue-specific sphingolipid depletion affects longevity. This project will contribute new insights into the relationships between aging, mitochondrial health, and sphingolipid metabolism. In the long run, these studies have the potential to inform new strategies for preserving mitochondria in aging cells to promote longevity and health span.