Scientists discover how cells repair the ‘recycling system’ promoting longevity

Fluorescence microscopy images showing the network of endoplasmic reticulum (green) wrapping around damaged lysosomes (red). The cell nucleus is shown in blue. Credit: Jay Xiaojun Tan

For the first time, researchers are describing a pathway by which cells repair damaged lysosomes, structures that contribute to longevity by recycling cellular waste. This discovery is an important step towards understanding and treating age-related diseases caused by leaky lysosomes. The study, conducted by scientists at the University of Pittsburgh, will be published today (September 7, 2022) in the journal Nature.

“I think these findings will have many implications for normal aging and age-related diseases.” — Toren Finkel, MD, Ph.D.

“Damage to lysosomes is a hallmark of aging and many diseases, especially neurodegenerative disorders such as Alzheimer’ssaid lead author Jay Xiaojun Tan, Ph.D. He is an assistant professor of cell biology at Pitt’s School of Medicine and a member of the Aging Institute, a partnership between Pitt and the University of Pittsburgh Medical Center ( UPMC). “Our study identifies a series of steps that we believe constitute a universal mechanism of lysosomal repair, which we named the PITT pathway in a snap at the University of Pittsburgh.”

Jay Xiaojun Tan

Jay Xiaojun Tan, Ph.D. Credit: UPMC

As the cell’s recycling system, lysosomes contain powerful digestive enzymes that break down molecular waste. This content is protected from damage to other parts of the cell by a membrane that acts like a chain-link fence surrounding 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 lead author Toren Finkel, MD, Ph.D. He is director of the Institute of Aging and Distinguished Professor of Medicine at Pitt’s School of Medicine.

First, Tan experimentally damaged lysosomes in cells grown in the lab and measured the proteins that arrived on the scene. He discovered that an enzyme called PI4K2A accumulates on damaged lysosomes within minutes and generates high levels of a signaling molecule called PtdIns4P.

“PtdIns4P is like a red flag. He says to the cell, ‘Hey, we have a problem here,’” Tan said. “This alert system then recruits another group of proteins called ORPs.”

ORP proteins function like tethers, Tan explained. One end of the protein binds to the red flag PtdIns4P on the lysosome, and the other end binds to the endoplasmic reticulum, which is the cellular structure involved in protein and lipid synthesis.

“The endoplasmic reticulum wraps around the lysosome like a blanket,” Finkel added. “Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, we found that they intertwine.”

Toren Finkel

Toren Finkel, MD, Ph.D. Credit: UPMC

Through this embrace, cholesterol and a lipid called phosphatidylserine are transported to the lysosome, where they help plug holes in the membrane barrier.

Phosphatidylserine also activates a protein called ATG2. It acts as 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.

“The beauty of this system is that all of the components of the PITT pathway were known to exist, but they were not known to interact in this sequence or for lysosome repair function,” Finkel said. . “I think these findings will have many implications for normal aging and age-related diseases.”

Scientists suspect that in healthy people, small ruptures in the lysosome membrane are rapidly repaired by the PITT pathway. However, if the damage is too great or the repair pathway is compromised – due to age or disease – the leaky lysosomes accumulate. In Alzheimer’s disease, the escape of tau fibrils from damaged lysosomes is a key step in disease progression.

When Tan deleted the gene encoding the first enzyme in the pathway, PI4K2A, he found that the spread of tau fibrils increased dramatically. This suggests that defects in the PITT pathway may contribute to the progression of Alzheimer’s disease. In future work, the scientists plan to develop mouse models to understand whether the PITT pathway can protect mice from developing Alzheimer’s disease.

Reference: “A phosphoinositide signaling pathway mediates rapid lysosomal repair” September 7, 2022, Nature.
DOI: 10.1038/s41586-022-05164-4

This research was supported by the National Institutes of Health (P30AG024827, R01HL142663, R01HL142589, U54AG075931, and K01AG075142) and the UPMC Competitive Medical Research Fund.