Overview
Our cells are complex microscopic structures that carry many functional components inside them, called organelles. Each organelle within a living cell works continuously to ensure our body can function and survive.
But what if our cell parts become dysfunctional and cannot be repaired? Despite not being desirable to our body, if such an event happens, the body will rely on the lysosomes, the cell components that recycle the “out-of-order” parts.
This article reviews a breakthrough in cellular repair in which scientists find a mechanism that corrects dysfunctional lysosomes to treat diseases and make longevity possible.
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Lysosomal Repair Can Be the Pathway to Anti-aging
What Are the Lysosomes?
The “Recycling Center” of a Cell
Lysosomes are membrane-bound cell organelles that play a vital role in various cellular processes. They can be found inside eukaryotic cells like those in animals but not in prokaryotic cells in plants.
As the “recycling center” of a cell, lysosomes break down molecular waste within a cell using their digestive enzymes to turn waste into the building blocks a cell needs to recreate new organelles and maintain its function.
Lysosomes also protect the cell from external materials, like invading viruses and bacteria, using the same enzymes for degrading the molecular waste.
Lysosomes Contain Acidic Enzymes
Lysosomes are different from other cell parts as these organelles are very acidic. To break down large molecules into smaller ones, the digestive enzymes inside the lysosomes, known as “hydrolytic enzymes,” need to burn through everything they touch.
Therefore, the membrane boundary surrounding the lysosomes is vital to their proximate organelles and the cell’s integrity. Any unwanted interaction between the lysosomal enzymes and the nearby organelles may result in their degradation or dysfunction.
Why Are They Important to the Cells?
Lysosomes Break Down Excess or Worn-out Cell Parts
As a recycling center of a cell, lysosomes ensure all the cell parts are working correctly.
If something goes wrong, lysosomes will be engaged in the breakdown and recycling of such dysfunctional cell components, making room for new organelles to generate in a natural process called autophagy (meaning “self-eating”).
The mitochondria are an example of this breakdown and recycling process. These organelles, found in almost every cell of an organism, usually function by creating the energy for cellular processes, hence known as the cell’s powerhouse.
However, the mitochondria may develop a fault for several reasons, including aging or genetic predisposition, leading to mitochondrial dysfunction. This is when the lysosomes step in and get rid of the worn-out mitochondria.
Lysosomes Destroy Invading Viruses and Bacteria
The lysosomes also serve as a defense mechanism against infection.
Viruses and bacteria can enter a cell by endocytosis, a process by which cells absorb particles from the outside by engulfing them with the cell membrane. If such invasion occurs, the lysosomes will fuse with the vesicle surrounding the viruses and bacteria and start delivering the enzymes to dissolve the invading particles.
So why do lysosomes have to fuse with the vesicle that wraps around the invading particles and not quickly deliver their enzymes? It is because directly removing the harmful particles will simultaneously blow away other healthy cell parts. Instead, fusing allows the acidic enzymes of lysosomes to be contained within the vesicle.
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Why is Lysosomal Dysfunction Detrimental?
Stressors Can Trigger Lysosomal Leakage
Recently, a process called “lysophagy” has been named after autophagy to describe the process that causes damage to the protective membrane of the lysosomes.
This process occurs following selective autophagy that targets the lysosomal membrane. The underlying mechanism of how lysophagy occurs and causes damage to the lysosomal membrane still needs to be fully understood.
Because inside the lysosomes are the cell-damaging enzymes, a ruptured membrane may cause their contents to escape to the environment inside the cell, a phenomenon known as lysosomal membrane permeabilization.
Lysosomal Membrane Permeabilization and Diseases
Lysosomal membrane permeabilization is a hallmark of lysosome-related diseases. Unlike the milder damage to the membrane that can be quickly and directly repaired in healthy cells, this leakage, if it becomes severe, cannot be resolved by itself.
The accumulation of leaky lysosomes has been associated with several neurodegenerative disorders, cancers, cardiovascular diseases, and aging-related diseases, collectively known as lysosomal storage diseases (LSDs).
How Are Lysosomes With Severe Leakage Repaired?
The PITT Pathway – A Universal Mechanism for Lysosomal Repair
Researchers at the University of Pittsburgh investigated how damaged lysosomes are naturally repaired to learn more about diseases caused by leaky lysosomes and develop a therapy option for this condition.
First, the research team intentionally damaged some lysosomes in lab-grown cells to examine how the repairing process naturally occurs in the damaged lysosomes.
Within minutes, an enzyme called PI4K2A had accumulated and generated high amounts of a signaling molecule called PtdIns4P. This signaling PtdIns4P is like a “red flag.” It alerts the cell about the issue and instructs the body to recruit ORPs, a set of repairing proteins.
Through the ORPs, the endoplasmic reticulum, the cellular component involved in protein and lipid synthesis, is then connected to the PtdIns4P on the lysosome.
The endoplasmic reticulum then wraps the lysosome. This is an exciting finding because the endoplasmic reticulum and lysosomes typically do not come close to each other. Still, when the lysosome is damaged, they begin to embrace.
Resealing Lysosomal Membrane Through Cholesterols and Lipids
In this arrangement, the endoplasmic reticulum wrapping around the lysosome makes it easier to transfer cholesterols and lipids to the lysosome, which are required to fix and reseal the ruptured lysosomal membrane.
Finally, a protein called ATG2, which functions as a bridge to carry more lipids to the lysosome to seal any remaining tears, is activated as the last step in the repair process.
The researchers describe the interactions between the cell components as “beautiful,” as these organelles have long existed but have never been recognized to display such an intricate interconnection for the lysosome repair process.
The entire mechanism is named the “PITT pathway” after the University of Pittsburgh. Researchers believe this is the universal mechanism for lysosomal repair, laying the groundwork for treating lysosome-related and age-related diseases.
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The PITT Pathway and Its Role in Alzheimer’s Disease
After identifying the PITT pathway, the researchers continued investigating its function in Alzheimer’s since the leakage of a substance called tau fibrils from damaged lysosomes is a crucial phase in the disease’s progression.
Tau is a protein that stabilizes microtubules, the microscopic tubular structures that provide the shape for eukaryotic cells. It is also well-known for forming fibrillar and insoluble aggregates in the brain, a hallmark of neurodegenerative disorders.
For this reason, tau is another substance that accumulates into plaques in Alzheimer’s disease along with the amyloid beta that we widely know. This substance harms brain cells needed for learning and memory, eventually leading to memory loss.
So what did the researchers find as they investigated the PITT pathway in Alzheimer’s?
Surprisingly, the spread of tau fibrils significantly increased after PI4K2A, the enzyme that initiates the PITT pathway, was removed, suggesting that any failure to recruit the PITT pathway may contribute to the development of Alzheimer’s.
To determine whether this lysosome-repairing pathway can be intentionally employed to stop the onset of Alzheimer’s disease in vulnerable individuals, the researchers plan to examine the mechanism again in mice models.
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Bottom Line: Lysosomal Repair in Anti-aging
Lysosomal repair not only paves the way for more efficient approaches to treating neurodegenerative diseases like Alzheimer’s but also is the foundation of eliminating lysosome-related diseases like lysosomal storage diseases (LSDs).
In addition, given that aging is the “catalyst” of various diseases, and reaching a certain age will shift human health to a more vulnerable state, lysosomal repair also plays a vital role in aging support and geriatric medicine.
Although research on lysosomal repair in diseases and aging is still in its infancy, more trials are warranted. If everything turns out alright, clinical experiments involving human subjects may take place and open a new door to achieving longevity.
References
Tan, J., Finkel, T. (2022). A Phosphoinositide Signaling Pathway Mediates Rapid Lysosomal Repair. Nature Journal.
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