Lysosomes digest material. Step one shows material entering a food vacuole through the plasma membrane, a process known as endocytosis. In step two a lysosome with an active hydrolytic enzyme comes into the pictures as the food vacuole moves away from the plasma membrane. Step three consists of the lysosome fusing with the food vacuole and hydrolytic enzymes entering the food vacuole. In the final step, step four, hydrolytic enzymes digest the food particles.[5]
Lysosomes are degradative organelles that act as the waste disposal system of the cell by digesting used materials in thecytoplasm, from both inside and outside the cell. Material from outside the cell is taken up throughendocytosis, while material from the inside of the cell is digested throughautophagy.[6] The sizes of the organelles vary greatly—the larger ones can be more than 10 times the size of the smaller ones.[7] They were discovered and named by Belgian biologistChristian de Duve, who eventually received theNobel Prize in Physiology or Medicine in 1974.
Lysosomes contain more than 60 different enzymes, and have more than 50 membrane proteins.[8][9] Enzymes of the lysosomes are synthesized in therough endoplasmic reticulum and exported to theGolgi apparatus upon recruitment by a complex composed ofCLN6 andCLN8 proteins.[10][11] The enzymes are transported from theGolgi apparatus to lysosomes in small vesicles, which fuse with larger acidic vesicles. Enzymes destined for a lysosome are tagged with the moleculemannose 6-phosphate, so that they are properly sorted into acidified vesicles.[12][13]
The wordlysosome (/ˈlaɪsoʊsoʊm/,/ˈlaɪzəzoʊm/) isNeo-Latin that uses thecombining formslyso- (referring tolysis and derived from the Latinlysis, meaning "to loosen", via Ancient Greek λύσις [lúsis]), and-some, fromsoma, "body", yielding "body that lyses" or "lytic body". The adjectival form islysosomal. The forms*lyosome and*lyosomal are much rarer; they use thelyo- form of the prefix but are often treated by readers and editors as mere unthinking replications oftypos, which has no doubt been true as often as not.
TEM views of various vesicular compartments. Lysosomes are denoted by "Ly". They are dyed dark due to their acidity; in the center of the top image, a Golgi Apparatus can be seen, distal from the cell membrane relative to the lysosome .
Christian de Duve, at the Laboratory of Physiological Chemistry at theCatholic University of Louvain in Belgium, had been studying the mechanism of action ofinsulin in liver cells. By 1949, he and his team had focused on the enzyme calledglucose 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 regulatingblood sugar levels. However, even after a series of experiments, they failed to purify and isolate the enzyme from the cellular extracts. Therefore, they tried a more arduous procedure ofcell fractionation, by which cellular components are separated based on their sizes usingcentrifugation.
They succeeded in detecting the enzyme activity from themicrosomal fraction. This was the crucial step in the serendipitous discovery of lysosomes. To estimate this enzyme activity, they used that of the standardized enzymeacid phosphatase and found that the activity was only 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, and led to the conclusion that a membrane-like barrier limited the accessibility of the enzyme to its substrate, and that the enzymes were able to diffuse after a few days (and react with their substrate). They described this membrane-like barrier as a "saclike structure surrounded by a membrane and containing acid phosphatase."[18]
It became clear that this enzyme from the cell fraction came from membranous fractions, which were definitely cell organelles, and in 1955 De Duve named them "lysosomes" to reflect their digestive properties.[19] The same year,Alex B. Novikoff from theUniversity of Vermont visited de Duve's laboratory, and successfully obtained the firstelectron micrographs of the new organelle. Using a staining method for acid phosphatase, de Duve and Novikoff confirmed the location of thehydrolytic enzymes of lysosomes usinglight and electron microscopic studies.[20][21] de Duve won theNobel Prize in Physiology or Medicine in 1974 for this discovery.
Originally, De Duve had termed the organelles the "suicide bags" or "suicide sacs" of the cells, for their hypothesized role inapoptosis.[22] However, it has since been concluded that they only play a minor role incell death.[23]
Lysosomes contain a variety of enzymes, enabling the cell to break down various biomolecules it engulfs, includingpeptides,nucleic acids,carbohydrates, andlipids (lysosomal lipase). The enzymes responsible for this hydrolysis require an acidic environment for optimal activity.
In addition to being able to break down polymers, lysosomes are capable of fusing with other organelles & digesting large structures or cellular debris; through cooperation withphagosomes, they are able to conductautophagy, clearing out damaged structures. Similarly, they are able to break down virus particles or bacteria inphagocytosis ofmacrophages.
The size of lysosomes varies from 0.1μm to 1.2μm.[24] With apH ranging from ~4.5–5.0, the interior of the lysosomes is acidic compared to the slightly basiccytosol (pH 7.2). The lysosomal membrane protects the cytosol, and therefore the rest of thecell, from thedegradative enzymes within the lysosome. The cell is additionally protected from any lysosomal acidhydrolases 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 destroyed in case there is leakage of the hydrolytic enzymes from the lysosome.
The lysosome maintains its pH differential by pumping inprotons (H+ ions) from the cytosol across themembrane viaproton pumps andchloride ion channels.Vacuolar-ATPases are responsible for transport of protons, while the counter transport of chloride ions is performed byClC-7 Cl−/H+ antiporter. In this way a steady acidic environment is maintained.[25][26]
It sources its versatile capacity for degradation by import of enzymes with specificity for different substrates;cathepsins are the major class of hydrolytic enzymes, whilelysosomal alpha-glucosidase is responsible for carbohydrates, andlysosomal acid phosphatase is necessary to release phosphate groups of phospholipids.
Recent research also indicates that lysosomes can act as a source of intracellular calcium.[27]
The lysosome is shown in purple, as an endpoint in endocytic sorting. AP2 is necessary for vesicle formation, whereas the mannose-6-receptor is necessary for sorting hydrolase into the lysosome's lumen.
Many components of animal cells are recycled by transferring them inside or embedded in sections of membrane. For instance, inendocytosis (more specifically,macropinocytosis), a portion of the cell's plasma membrane pinches off to form vesicles 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 fromendosomes.[28][29]
The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes are transcribed in thenucleus in a process that is controlled by transcription factor EB (TFEB).[14] mRNA transcripts exit the nucleus into the cytosol, where they are translated byribosomes. The nascent peptide chains aretranslocated into the roughendoplasmic reticulum, where they are modified. Lysosomal soluble proteins exit the endoplasmic reticulum viaCOPII-coated vesicles after recruitment by theEGRESS complex (ER-to-Golgirelaying ofenzymes of the lysosomalsystem), which is composed ofCLN6 andCLN8 proteins.[10][11] COPII vesicles then deliver lysosomal enzymes to theGolgi apparatus, where a specific lysosomal tag,mannose 6-phosphate, is added to the peptides. The presence of these tags allow for binding tomannose 6-phosphate receptors in the Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for the lysosomal system.[30]
Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with alate 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.[30] The late endosome itself can eventually grow into a mature lysosome, as evidenced by the transport of endosomal membrane components from the lysosomes back to the endosomes.[28]
As the endpoint of endocytosis, the lysosome also acts as a safeguard in preventing pathogens from being able to reach the cytoplasm before being degraded. Pathogens often hijack endocytic pathways such aspinocytosis in order to gain entry into the cell. The lysosome prevents easy entry into the cell by hydrolyzing the biomolecules of pathogens necessary for their replication strategies; reduced lysosomal activity results in an increase in viral infectivity, including HIV.[31] In addition,AB5 toxins such ascholera hijack the endosomal pathway while evading lysosomal degradation.[31]
Lysosomes are involved in a group of genetically inherited deficiencies, or mutations calledlysosomal storage diseases (LSD),inborn errors of metabolism caused by a dysfunction of one of the enzymes. The rate of incidence is estimated to be 1 in 5,000 births, and the true figure expected to be higher as many cases are likely to be undiagnosed or misdiagnosed. The primary cause is deficiency of anacid hydrolase. Other conditions are due to defects in lysosomal membrane proteins that fail to transport the enzyme, non-enzymatic soluble lysosomal proteins. The initial effect of such disorders is accumulation of specific macromolecules or monomeric compounds inside the endosomal–autophagic–lysosomal system.[15] This results in abnormal signaling pathways,calcium homeostasis,lipid biosynthesis and degradation and intracellular trafficking, ultimately leading to pathogenetic disorders. The organs most affected arebrain,viscera, bone andcartilage.[32][33]
There is no direct medical treatment to cure LSDs.[34] The most common LSD isGaucher's disease, which is due to deficiency of the enzymeglucocerebrosidase. Consequently, the enzyme substrate, the fatty acidglucosylceramide accumulates, particularly inwhite blood cells, which in turn affects spleen, liver, kidneys, lungs, brain and bone marrow. The disease is characterized by bruises, fatigue,anaemia, low blood platelets,osteoporosis, and enlargement of the liver and spleen.[35][36] As of 2017,enzyme replacement therapy is available for treating 8 of the 50-60 known LDs.[37]
Dysfunctional lysosome activity is also heavily implicated in the biology ofaging, and age-related diseases such as Alzheimer's, Parkinson's, and cardiovascular disease.[17][39]
Weakbases withlipophilic 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 calledlysosomotropism,[41] "acid trapping" or "proton pump" effect.[42] The amount of accumulation of lysosomotropic compounds may be estimated using a cell-based mathematical model.[43]
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-lives; these properties have been found for drugs such ashaloperidol,[44]levomepromazine,[45] andamantadine.[46] 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 lysosomally accumulated drugs.[47][48] Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[49] and include for examplefluoxetine,sertraline, oramitriptyline.
Ambroxol is a lysosomotropic drug of clinical use to treat conditions of productive cough for its mucolytic action. Ambroxol triggers the exocytosis of lysosomes via neutralization of lysosomal pH andcalcium release from acidic calcium stores.[50] Presumably for this reason,Ambroxol was also found to improve cellular function in some disease of lysosomal origin such asParkinson's orlysosomal storage disease.[51][52]
Impaired lysosome function is prominent in systemic lupus erythematosus preventing macrophages and monocytes from degrading neutrophil extracellular traps[53] and immune complexes.[54][55][56] The failure to degrade internalized immune complexes stems from chronic mTORC2 activity, which impairs lysosome acidification.[57] As a result, immune complexes in the lysosome recycle to the surface of macrophages causing an accumulation of nuclear antigens upstream of multiple lupus-associated pathologies.[54][58][59]
By scientific convention, the term lysosome is applied to these vesicular organelles only in animals, and the termvacuole is applied to those in plants, fungi and algae (some animal cells also have vacuoles). Discoveries in plant cells since the 1970s started to challenge this definition. Plant vacuoles are found to be much more diverse in structure and function than previously thought.[60][61] Some vacuoles contain their own hydrolytic enzymes and perform the classic lysosomal activity, which is autophagy.[62][63][64] These vacuoles are therefore seen as fulfilling the role of the animal lysosome. Based on de Duve's description that "only when considered as part of a system involved directly or indirectly in intracellular digestion does the term lysosome describe a physiological unit", some botanists strongly argued that these vacuoles are lysosomes.[65] However, this is not universally accepted as the vacuoles are strictly not similar to lysosomes, such as in their specific enzymes and lack of phagocytic functions.[66] Vacuoles do not have catabolic activity and do not undergoexocytosis as lysosomes do.[67]
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