PITTSBURGH, Sept. 7, 2022 — Today in Nature, University of Pittsburgh researchers describe for the first time a pathway by which cells repair damaged lysosomes, structures that contribute to longevity by recycling cellular trash. The findings are an important step towards understanding and treating age-related diseases driven by leaky lysosomes.
“Lysosome damage is a hallmark of aging and many diseases, particularly neurodegenerative disorders such as Alzheimer’s,” said lead author Jay Xiaojun Tan, Ph.D., assistant professor of cell biology at Pitt’s School of Medicine and member of the Aging Institute, a partnership between Pitt and UPMC. “Our study identifies a series of steps that we believe is a universal mechanism for lysosomal repair, which we named the PITT pathway as a nod to the University of Pittsburgh.”
As the cell’s recycling system, lysosomes contain potent digestive enzymes that degrade molecular waste. These contents are walled off from damaging other parts of the cell with a membrane that acts like a chain link fence around a hazardous waste facility. Although breaks can occur in this fence, a healthy cell quickly repairs the damage. To learn more about this repair process, Tan teamed up with senior author Toren Finkel, M.D., Ph.D., director of the Aging Institute and distinguished professor of medicine at Pitt’s School of Medicine.
First, Tan experimentally damaged lysosomes in lab-grown cells and then measured the proteins that arrived on the scene. He found that an enzyme called PI4K2A accumulated on damaged lysosomes within minutes and generated high levels of a signaling molecule called PtdIns4P.
“PtdIns4P is like a red flag. It tells the cell, ‘Hey, we have a problem here,’” said Tan. “This alert system then recruits another group of proteins called ORPs.”
ORP proteins work like tethers, Tan explained. One end of the protein binds to the PtdIns4P red flag on the lysosome, and the other end binds to the endoplasmic reticulum, the cellular structure involved in synthesis of proteins and lipids.
“The endoplasmic reticulum wraps around the lysosome like a blanket,” added Finkel. “Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, we found that they were embracing.”
Through this embrace, cholesterol and a lipid called phosphatidylserine are shuttled to the lysosome and help patch up holes in the membrane fence.
Phosphatidylserine also activates a protein called ATG2, which acts like a bridge to transfer other lipids to the lysosome, the final membrane repair step in the newly described PITT — or phosphoinositide-initiated membrane tethering and lipid transport — pathway.
“What’s beautiful about this system is that all of the components of the PITT pathway were known to exist, but they weren’t known to interact in this sequence or for the function of lysosome repair,” said Finkel. “I believe these findings are going to have many implications for normal aging and for age-related diseases.”
The researchers suspect that in healthy people, small breaks in the lysosome membrane are quickly repaired through the PITT pathway. But if the damage is too extensive or the repair pathway is compromised — due to age or disease — leaky lysosomes accumulate. In Alzheimer’s, leakage of tau fibrils from damaged lysosomes is a key step in progression of the disease.
When Tan deleted the gene encoding the first enzyme in the pathway, PI4K2A, he found that tau fibril spreading increased dramatically, suggesting that defects in the PITT pathway could contribute to Alzheimer’s disease progression. In future work, the researchers plan to develop mouse models to understand whether the PITT pathway can protect mice from developing Alzheimer’s disease.
This research was supported by the National Institutes of Health (P30AG024827, R01HL142663, R01HL142589, U54AG075931 and K01AG075142) and the UPMC Competitive Medical Research Fund.
About the University of Pittsburgh School of Medicine
As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top recipients of funding from the National Institutes of Health since 1998. In rankings released by the National Science Foundation, Pitt is in the upper echelon of all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see www.medschool.pitt.edu.
A $24 billion health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. The largest nongovernmental employer in Pennsylvania, UPMC integrates more than 92,000 employees, 40 hospitals, 800 doctors’ offices and outpatient sites, and a more than 4 million-member Insurance Services Division, the largest medical insurer in western Pennsylvania. In the most recent fiscal year, UPMC contributed $1.5 billion in benefits to its communities, including more care to the region’s most vulnerable citizens than any other health care institution, and paid more than $900 million in federal, state and local taxes. Working in close collaboration with the University of Pittsburgh Schools of the Health Sciences, UPMC shares its clinical, managerial, and technological skills worldwide through its innovation and commercialization arm, UPMC Enterprises, and through UPMC International. U.S. News consistently ranks UPMC Presbyterian Shadyside among the nation’s best hospitals in many specialties and ranks UPMC Children’s Hospital of Pittsburgh on its Honor Roll of America’s Best Children’s Hospitals. For more information, go to UPMC.com.
A phosphoinositide signaling pathway mediates rapid lysosomal repair