PITT fix

A how-to guide for patching cell leaks

Caption: Damaged lysosomes (red) near cell nuclei (blue) get repaired with help from the endoplasmic reticulum network (green). (Photo credit: Jay Xiaojun Tan)

A leaky lysosome can spell trouble inside a cell, but usually the repair process is quick and easy.

In healthy people, cells undergo needed maintenance without a hitch. But disease and aging can put this process in jeopardy.

Now, Pitt Med researchers have created a how-to guide for the fix, describing for the first time the pathway that cells take to mend the leaks. Published in the journal Nature in September, their findings could help scientists understand and treat age-related diseases like Alzheimer’s.

Considered the cell’s recycling system, lysosomes contain digestive enzymes that break down molecular waste. A membrane around the lysosome normally keeps those enzymes from damaging other parts of the cell, but leaks do sometimes appear.

To see how the repair process springs into action, Jay Xiaojun Tan, a PhD and the study’s lead author, experimentally damaged lysosomes in lab-grown cells. He found that an enzyme quickly accumulated on the injured organelles and generated high levels of a signaling molecule that Tan compared to a “red flag.”

“It tells the cell, ‘Hey, we have a problem here,’” says Tan, assistant professor of cell biology and member of the Pitt/UPMC Aging Institute. “This alert system then recruits another group of proteins, called ORPs.” The ORPs tether the lysosome to the cell’s endoplasmic reticulum, which allows lipids and proteins to reach and patch the leaks. The researchers named the sequence of steps the “PITT pathway.” (PITT, in this case, stands for phosphoinositide-initiated membrane tethering and lipid transport.)

When age or disease causes major damage or compromises the pathway, the leaks can mount and lead to further problems. Leaks of misfolded proteins (specifically, tau fibrils), for example, spur the progression of Alzheimer’s disease.

Tan collaborated on the study with senior author Toren Finkel, an MD, PhD, director of the Aging Institute and Distinguished Professor of Medicine. In the future, the researchers plan to investigate whether manipulating this pathway can protect mice from developing Alzheimer’s.  

—Staff reports

Read more from the Winter 2022/23 issue.