May 1, 2025
Some Organelles Might Need a Workout
Pitt researcher Jay Xiaojun Tan is working to make people healthier, cell by cell.
TOPICS: Aging & Lifespan | School of Medicine
By Strategic Communications
When we exercise, we put manageable stress on our body, preparing it to handle more stress in the years to come. The University of Pittsburgh’s Jay Xiaojun Tan, assistant professor of cell biology, School of Medicine, thinks the same principle applies to lysosomes, organelles that break down waste material in cells.
Throughout our lives, our lysosomes also face stress and damage, with consequences mounting during aging that impair their function. But what if some stress, earlier on, benefits them? Certain drugs, such as the type II diabetes drug metformin, appear to give lysosomes a mild workout in ways that protect them from future damage.
“The cells have an acute response to repair or remove damage, but they also trigger short-term and long-term changes that help them deal with future similar damages,” says Tan, who came to Pitt in 2019 and started his own lab in 2022. “Our goal is to find what types of lysosomal stress and what level of stress can make these lysosomes healthier and make the whole cells healthier.”
In recent work with Toren Finkel, director of the Pitt’s Aging Institute, Tan has reviewed pathways that allow lysosomes to repair damaged cells and clear cellular stress. In a 2022 paper in Nature, he identified how lysosomes repair their own leaks in a process dubbed the “PITT pathway.” (PITT stands for phosphoinositide-initiated membrane tethering and lipid transport.) With support from a Maximizing Investigators’ Research Award from the National Institute of General Medical Sciences, he’s now seeing how PITT communicates with other pathways to allow oil-like droplets of proteins in the cytosol to patch holes in membranes.
“Our goal is to find what types of lysosomal stress and what level of stress can make these lysosomes healthier and make the whole cell healthier.”
Jay Xiaojun Tan, assistant professor of cell biology
In October 2024, he published a paper in Molecular Cell that revealed a protein called STING starts a process that activates genes to produce more lysosomes, which helps clear stress in the cell. STING was already known to be involved in an antiviral response that triggers inflammation to fight infections and diseases. In aging and neurodegenerative diseases, that pathway can become chronically “on,” so some scientists are working on interventions to block STING. Tan’s findings suggest that might not be the best idea. Because the protein also promotes cell health by clearing stress, it may be better to selectively target its inflammatory effects rather than ditching it altogether.
After learning how these pathways contribute to healthy aging in cells, Tan is now determined to find out whether a little lysosome workout could make these pathways even stronger in the long run.