New research, published today in the journal Science , shows how lysosomes — organelles that act like cells' waste disposal system — respond to stress by becoming abnormally bloated, a process called lysosomal vacuolation that is associated with numerous diseases.
Essential for cellular health, well-functioning lysosomes are also linked with healthy aging, so better understanding of the steps involved in vacuolation could eventually inform new therapies to treat diseases or promote healthy aging, according to senior author Jay Xiaojun Tan, Ph.D., assistant professor in the Department of Cell Biology at the University of Pittsburgh School of Medicine and member of the Aging Institute , a partnership between Pitt and UPMC. He elaborates on the study findings in the following Q&A.
What is a vacuole, and what is lysosomal vacuolation?
A vacuole is a membrane-bound compartment inside cells, like a water balloon, that stores water, molecules or waste. In plant cells, the central vacuole is large and helps store nutrients, regulate pressure and maintain structural rigidity. Animal cells don't usually have vacuoles, but they contain related compartments called lysosomes. Lysosomal vacuolation refers to a condition in which lysosomes become abnormally enlarged like overinflated balloons, resembling plant vacuoles.
What role do lysosomes play in cells, and how does lysosomal vacuolation affect their function?
Lysosomes are essential for cell health. Like a waste disposal system, they digest damaged proteins, worn-out parts and invading microbes. By degrading a broad range of macromolecules, lysosomes preserve cellular function and longevity. Lysosomal vacuolation is thought to be an indication of stress or dysfunction of lysosomes, and these vacuoles are found in a large spectrum of medical conditions, including lysosomal storage disorders, aging, infection, chemotherapy, cataracts, cadmium toxicity, prion diseases and other neurodegenerative conditions such as Parkinson's and Alzheimer's disease.
Why are you interested in understanding lysosomal stress?
Since lysosomes are "longevity-promoting" organelles, we are particularly interested in processes that could enhance lysosomal integrity and activity. One of my lab's guiding visions in recent years is that mild lysosomal stress may actually be beneficial by triggering adaptive responses that improve lysosomal quality and function. We are exploring how cells respond to various forms of lysosomal stress, with the hope that some of these protective mechanisms can eventually be harnessed to promote human health and longevity.
What was the goal of this study?
Lysosomal vacuolation has been observed in many diseases and has puzzled scientists for decades. However, we still don't know whether it is harmful or beneficial, largely because the mechanisms behind vacuole formation remain poorly understood. Without a molecular handle, it has not been possible to selectively remove these swollen lysosomes in order to test their physiological and pathological roles. Our goal was to uncover the underlying mechanism of lysosomal vacuolation — an advance that now allows us to investigate what these vacuoles actually do in disease and whether targeting the vacuolation process could offer therapeutic potential for disease treatment or healthy aging.
What were the main findings?
We found that cells have a well-developed system to drive lysosomal vacuolation. In response to many different types of stress, lysosomes become filled up with solutes, which draws in water and stretches the lysosomal membrane — like inflating a balloon. The potential risk of lysosomal rupture is detected by a protein we named LYVAC, or lysosomal vacuolator. LYVAC attaches to these stressed lysosomes, where it delivers lipids, which serve as membrane building blocks to allow lysosomal expansion in a controlled way. This process of lysosomal vacuolation is a natural, highly regulated response. LYVAC plays a central role in this process, helping cells adapt to stress and maintain lysosomal stability.
Were you surprised by any of the results?
Yes! We were especially surprised to find that lysosomal swelling isn't just a passive defect of the cell — it's actually a tightly controlled process. The cell seems to know exactly which lysosomes are in trouble and sends the protein LYVAC to help only those. LYVAC does two things: it sticks to the stressed lysosome and then helps move lipids to it so the membrane can grow and form a vacuole. Both steps need two separate signals to happen, which keeps everything precise and prevents LYVAC from acting on healthy parts of the cell. We didn't expect this kind of accuracy, and it was really exciting to see.
What are the implications of these findings?
By targeting LYVAC, we can begin to understand the exact roles that lysosomal vacuoles play in different diseases. If vacuole formation turns out to be a key driver of disease, then blocking LYVAC could offer a promising new treatment strategy.
What's next for this research?
We're continuing to explore how LYVAC is controlled — what turns it on, and how it recognizes which lysosomes are under stress. We're also testing whether LYVAC is helpful or harmful in a genetic model of neurodegeneration, where large lysosomal vacuoles naturally appear. Our goal is to find ways to adjust how lipids move into lysosomes, either to prevent harmful swelling or to help lysosomes recover in stressed or diseased cells. This research builds on our previous discovery of the PITT pathway , which showed how cells can rapidly repair lysosomes after damage. Together, these studies suggest that cells have multiple lipid-based systems to respond to different types of lysosomal stress. By better understanding these processes, we hope to uncover new strategies to protect cells and promote healthy aging.
Other authors on the study were Haoxiang Yang, Jinrui Xun, M.D., Awishi Mondal, M.S., Bo Lv, Ph.D., and Simon Watkins, Ph.D., all of Pitt and UPMC; and Yajuan Li, Ph.D., and Lingyan Shi, Ph.D., both of the University of California San Diego.
This research was supported by the National Institutes of Health (1K01AG075142, R35GM150506, R01NS111039, R01 GM149976, R21NS125395 and U01AI167892), start-up funding from the Aging Institute and a UPMC Competitive Medical Research Fund award.
