PITT pathway: Scientists discover how cells repair longevity-promoting ‘recycling system’

By | 07/09/2022

Endoplasmic Reticulum Network Wrapping Around Damaged Lysosomes

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

For the first time, researchers draw a pathway by which cells repair damaged lysosomes, structures that contribute to longevity by recycling cellular trash. The discovery is an important step toward understanding and treating age-related diseases driven by leaky lysosomes. The study, by scientists from the University of Pittsburgh, will be published today (September vii, 2022) in the journal
Nature.

“I believe these findings are going to accept many implications for normal aging and for historic period-related diseases.” —
Toren Finkel, M.D., Ph.D.

“Lysosome harm is a hallmark of aging and many diseases, particularly neurodegenerative disorders such as

Jay Xiaojun Tan

Jay Xiaojun Tan, Ph.D. Credit: UPMC

As the cell’s recycling system, lysosomes contain powerful 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 surrounding a hazardous waste material facility. Even though breaks can occur in this fence, a salubrious cell quickly repairs the damage. To learn more most this repair process, Tan teamed up with senior writer Toren Finkel, M.D., Ph.D. He is managing director of the Aging Plant and distinguished professor of medicine at Pitt’south School of Medicine.

First, Tan experimentally damaged lysosomes in lab-grown cells and measured the proteins that arrived on the scene. He discovered 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 and so recruits another group of proteins chosen ORPs.”

ORP proteins function 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, which is the cellular structure involved in synthesis of proteins and lipids.

“The endoplasmic reticulum wraps around the lysosome similar a coating,” added Finkel. “Normally, the endoplasmic reticulum and lysosomes barely touch each other, just once the lysosome was damaged, nosotros found that they were embracing.”

Toren Finkel

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

Through this embrace, cholesterol and a lipid called phosphatidylserine are shuttled to the lysosome, where they assist patch upwardly holes in the membrane fence.

Phosphatidylserine too activates a protein chosen ATG2. It 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’southward cute well-nigh this system is that all of the components of the PITT pathway were known to be, 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 take many implications for normal crumbling and for age-related diseases.”

The scientists suspect that in healthy people, small breaks in the lysosome membrane are quickly repaired through the PITT pathway. Nevertheless, if the harm is likewise extensive or the repair pathway is compromised — due to age or disease — leaky lysosomes accrue. In Alzheimer’s, leakage of tau fibrils from damaged lysosomes is a primal step in the progression of the disease.

When Tan deleted the gene encoding of the first enzyme in the pathway, PI4K2A, he discovered that tau fibril spreading increased dramatically. This suggests that defects in the PITT pathway could contribute to Alzheimer’due south disease progression. In future work, the scientists programme to develop mouse models to empathize whether the PITT pathway tin can protect mice from developing Alzheimer’s disease.

Reference: “A phosphoinositide signaling pathway mediates rapid lysosomal repair” vii September 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.

Source: https://scitechdaily.com/scientists-discover-how-cells-repair-longevity-promoting-recycling-system/