Lysosomes

Lysosomes

Template:Organelle diagramLysosomes (derived from the Greek words lysis, meaning "to separate", and soma, "body") are the cell's waste disposal system and can digest some compounds. They are used for the digestion of macromolecules from phagocytosis (ingestion of other dying cells or larger extracellular material, like foreign invading microbes), endocytosis (where receptor proteins are recycled from the cell surface), and autophagy (wherein old or unneeded organelles or proteins, or microbes that have invaded the cytoplasm are delivered to the lysosome).

Other functions include digesting bacteria (or other forms of waste) that invade a cell and helping repair damage to the plasma membrane by serving as a membrane patch, sealing the wound. In the past, lysosomes were thought to kill cells that are no longer wanted, such as those in the tails of tadpoles or in the web from the fingers of a 3- to 6-month-old fetus.

Discovery

Christian de Duve, then chairman of the Laboratory of Physiological Chemistry at the Catholic University of Louvain in Belgium, had been studying the mechanism of action of a pancreatic hormone insulin in liver cells. By 1949 he and his team had focussed on the enzyme called glucose 6-phosphatase, which is the first crucial enzyme in sugar metabolism and the target of insulin. They already suspected that this enzyme played a key role in regulating blood sugar levels. However, even after a series of experiments, they failed to purify and isolate the enzyme from the cellular extracts. Therfore they tried a more arduous procedure of cell fractionation, by which cellular components are separated based on their sizes using centrifugation. They succeeded in detecting the enzyme activity from the microsomal fraction. This was the crucial step in the serendipitous discovery. To estimate the enzyme activity, they used that of standardadised enzyme acid phosphatase, and found that the activity was quite low (10% of the expected value). One day, the enzyme activity of purified cell fractions which had been refrigerated for five days was measured. Surprisingly the enzyme activity was increased to normal of that of the fresh sample. The result was the same no matter how many times they repeated the estimation. This led to the conclusion that a membrane-like barrier limited the accessibility of the enzyme to its substrate, so that the enzymes were able to diffuse after a few days. They described the membrane-like barrier as a "saclike structure surrounded by a membrane and containing acid phosphatase."[1] It became obvious that an unrelated enzyme from the cell fraction came from a membranous fractions which were definitely cell organelles, and in 1955 De Duve named them "lysosomes" to reflect their digestive properties.[2] That same year, Alex B. Novikoff from the University of Vermont visited de Duve´s laboratory, and sucessfully obtained the first electron micrographs of the new organelle. Using a staining method for acid phosphatase, de Duve and Novikoff confirmed the location of the hydrolytic enzymes of lysosomes using light and electron microscopic studies.[3][4] de Duve won the Nobel Prize in Physiology or Medicine in 1974 for this discovery.

Function and structure

Lysosomes are cellular organelles that contain acid hydrolase enzymes that break down waste materials and cellular debris. They can be described as the stomach of the cell. They are found in animal cells, while their existence in yeasts and plants is disputed. Some biologists say the same roles are performed by lytic vacuoles,[5] while others suggest there is strong evidence that lysosomes are indeed found in some plant cells.[6] Lysosomes digest excess or worn-out organelles, food particles, and engulf viruses or bacteria. The membrane around a lysosome allows the digestive enzymes to work at the pH they require. Lysosomes fuse with autophagic vacuoles and dispense their enzymes into the autophagic vacuoles, digesting their contents. They are frequently nicknamed "suicide-bags" or "suicide-sacs" by cell biologists due to their autolysis. A group of genetic inherited disorders called lysosomal storage diseases (LSD) results from the dysfunction of lysosomes.

The size of a lysosome varies from 0.1–1.2 μm.[7] At pH 4.8, the interior of the lysosomes is acidic compared to the slightly basic cytosol (pH 7.2). The lysosome maintains this pH differential by pumping protons (H+ ions) from the cytosol across the membrane via proton pumps and chloride ion channels. The lysosomal membrane protects the cytosol, and therefore the rest of the cell, from the degradative enzymes within the lysosome. The cell is additionally protected from any lysosomal acid hydrolases that drain into the cytosol, as these enzymes are pH-sensitive and do not function well or at all in the alkaline environment of the cytosol.This ensures that cytosolic molecules and organelles are not lysed in case there is leakage of the hydrolytic enzymes from the lysosome.

Formation

Many components of animal cells are recycled by transferring them inside or embedded in sections of membrane. For instance, in endocytosis, a portion of the cell’s plasma membrane pinches off to form a vesicle that will eventually fuse with an organelle within the cell. Without active replenishment, the plasma membrane would continuously decrease in size. It is thought that lysosomes participate in this dynamic membrane exchange system and are formed by a gradual maturation process from endosomes.[8]

The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes are transcribed in the nucleus. mRNA transcripts exit the nucleus into the cytosol, where they are translated by ribosomes. The nascent peptide chains are translocated into the rough endoplasmic reticulum, where they are modified. Upon exiting the endoplasmic reticulum and entering the Golgi apparatus via vesicular transport, a specific lysosomal tag, mannose 6-phosphate, is added to the peptides. The presence of these tags allow for binding to mannose 6-phosphate receptors in the Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for the lysosomal system.[9]

Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with a late endosome, a relatively acidic organelle with an approximate pH of 5.5. This acidic environment causes dissociation of the lysosomal enzymes from the mannose 6-phosphate receptors. The enzymes are packed into vesicles for further transport to established lysosomes.[9] The late endosome itself can eventually mature into a mature lysosome, as evidenced by the transport of endosomal membrane components from the lysosomes back to the endosomes.[8]

Lysosomotropism

Weak bases with lipophilic properties accumulate in acidic intracellular compartments like lysosomes. While the plasma and lysosomal membranes are permeable for neutral and uncharged species of weak bases, the charged protonated species of weak bases do not permeate biomembranes and accumulate within lysosomes. The concentration within lysosomes may reach levels 100 to 1000 fold higher than extracellular concentrations. This phenomenon is called "lysosomotropism"[10] or "acid trapping". The amount of accumulation of lysosomotropic compounds may be estimated using a cell based mathematical model.[11]

A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties. This explains a number of pharmacological properties of these drugs, such as high tissue-to-blood concentration gradients or long tissue elimination half-lifes; these properties have been found for drugs such as haloperidol,[12] levomepromazine, [13] and amantadine.[14] However, high tissue concentrations and long elimination half-lives are explained also by lipophilicity and absorption of drugs to fatty tissue structures. Important lysosomal enzymes, such as acid sphingomyelinase, may be inhibited by lysososomally accumulated drugs.[15][16] Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[17] and include for example fluoxetine, sertraline, or amitriptyline.

References

External links

  •  This article incorporates "Science Primer".
  • 3D structures of proteins associated with lysosome membrane
  • Hide and Seek Foundation For Lysosomal Research Team
  • Self-Destructive Behavior in Cells May Hold Key to a Longer Life
  • Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
  • Animation showing how lysosomes are made, and their function

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