Understanding sphingolipid-dependent remodeling of mitochondria in aging cells

One of the hallmarks of aging is a decline in the function of mitochondria, which is associated with changes in mitochondria morphology as cells age. However, mechanisms contributing to mitochondrial dysfunction in aging cells are not well understood. We have determined that interventions that lower sphingolipid levels preserve mitochondrial function and morphology in aging cells leading us to hypothesize that localized accumulation of sphingolipids contributes to the decline of mitochondrial function during aging. Mechanisms contributing to mitochondrial sphingolipid homeostasis during aging are not well understood. However, our results suggest that targeting lipid transfer activities at inter-organelle junctions which control the flux of sphingolipids into and out of mitochondria could promote longevity and healthspan. This highly collaborative project will leverage live cell imaging, genetics, and quantitative mass spectrometry approaches across two complementary aging models to test our central hypothesis and address the mechanisms that couple sphingolipid metabolism and mitochondrial health during aging. In the first aim, we will dissect the mechanism of sphingolipid-dependent changes in mitochondrial morphology as cells age, focusing on the role of sphingolipid trafficking and alterations to lipid composition of mitochondrial membranes. This aim will also dissect mechanisms for restoring young mitochondria after age-associated mitochondria remodeling has occurred. In the second aim, we will define mechanisms that drive mitochondria remodeling during oxidative stress. These studies will contribute to a deeper understanding of the relationships between sphingolipid metabolism and oxidative stress in aging cells. In the third aim, we will examine the relationship between sphingolipid metabolism and mitochondrial stress responses. This project will contribute new insights into the relationships between aging, mitochondrial health, and sphingolipid metabolism, with the long-term goal of informing novel strategies for preserving mitochondria function in aging cells. Project Number: 1R01AG092718-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jason MacGurn (+2 co-PIs) | Institution: VANDERBILT UNIVERSITY, Nashville, TN | Award Amount: $482,800 | Activity Code: R01 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295253