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Understanding a Natural Mechanism of Lysosomal Repair


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Posted 21 September 2022 - 07:09 PM


Lysosomes are membrane-bound packages of enzymes found in cells. They recycle damaged and excess molecules and structures in the cell by breaking them down into raw materials that can be reused for protein synthesis. This activity is vital to cell health, and dysfunction of lysosomes is a noted feature of aging. Thus it is interesting to see a greater understanding of the ways in which cells maintain lysosomes, as outlined in today's research materials. The focus is on the repair of lysosomal membranes, a process that may break down with age, and thus some degree of benefit might be achieved by enhancing this repair. The first step on that road is to understand which proteins are involved, and thus might be targets for manipulation.

That said, it is isn't at all clear that this issue of membrane damage is the important aspect of lysosomal decline in later life. Another issue involves the accumulation of cellular waste materials that the lysosome cannot break down, which occurs in inherited lysosomal storage conditions due to loss of function mutation that robs an individual of one or more essential lysosomal enzymes, but also over the course of aging in long-lived cells. In old individuals, this mix of problem waste molecules is called lipofuscin, and lysosomes become bloated with it, unable to perform their usual tasks. Cells fall into a garbage catastrophe and become dysfunctional or die. Membrane repair is most likely not all that relevant to lysosomal performance in this situation.

Scientists Discover How Cells Repair Longevity-Promoting 'Recycling System'

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. An enzyme called PI4K2A accumulated on damaged lysosomes within minutes and generated high levels of a signaling molecule called PtdIns4P, which recruits other molecules called ORPs. ORP proteins work like tethers. 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. Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, researchers 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.

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.

A phosphoinositide signalling pathway mediates rapid lysosomal repair

Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.

Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11, and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair.

Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.


View the full article at FightAging




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