Lysosomes are cellular organelles that contain acid hydrolase enzymes to break down waste materials and cellular debris. They are found in animal cells, while in yeast and plants the same roles are performed by lytic vacuoles.[1] 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 4.5 pH they require. Lysosomes fuse with vacuoles and dispense their enzymes into the vacuoles, digesting their contents. They are created by the addition of hydrolytic enzymes to early endosomes from the Golgi apparatus. The name lysosome derives from the Greek words lysis, to separate, and soma, body. They are frequently nicknamed "suicide-bags" or "suicide-sacs" by cell biologists due to their autolysis. Lysosomes were discovered by the Belgian cytologist Christian de Duve in the 1960s.
The size of lysosomes varies from 0.1–1.2 μm.[2] At pH 4.8, the interior of the lysosomes is acidic compared to the slightly alkaline 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.
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Some important enzymes found within lysosomes include:
Lysosomal enzymes are synthesized in the cytoplasm and the endoplasmic reticulum, where they receive a mannose-6-phosphate in the Golgi apparatus that targets them for the late endosome or lysosome formation. Aberrant lysosomal targeting causes inclusion-cell disease, whereby enzymes do not properly reach the lysosome.
Lysosomes 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 (where in old or unneeded organelles or proteins, or microbes that have invaded the cytoplasm are delivered to the lysosome). Autophagy may also lead to autophagic cell death, a form of programmed self-destruction, or autolysis, of the cell, which means that the cell is digesting itself.
Other functions include digesting foreign 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.
There are a number of lysosomal storage diseases that are caused by the malfunction of the lysosomes or one of their digestive proteins; examples include Niemann Pick Type C, Tay-Sachs disease and Pompe's disease. These diseases are caused by a defective or missing digestive protein, which leads to the accumulation of substrates within the cell, impairing metabolism.
In the broad sense, these can be classified as mucopolysaccharidoses, GM2 gangliosidoses, lipid storage disorders, glycoproteinoses, mucolipidoses, or leukodystrophies.
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"[3] or "acid trapping". The amount of accumulation of lysosomotropic compounds may be estimated using a cell based mathematical model.[4]
A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties. This explaines 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,[5] levomepromazine [6] and amantadine.[7] However, in addition to lysosomotropism, high tissue concentrations and long elimination half-life is 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.[8][9] Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[10] and include for example fluoxetine, sertraline or amitriptyline.
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