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{{short description|Cell membrane organelle}}▼
{{Distinguish|Lysozyme|lectins}}
▲{{short description|Cell organelle}}
{{Use dmy dates|date=August 2017}}
{{Organelle diagram}}
A '''lysosome''' ({{IPAc-en|ˈ|l|aɪ|s|ə|ˌ|s|oʊ|m}}) is a single [[membrane-bound organelle]] found in many<!--
[[File:Lysosomes Digestion.svg|thumb|Lysosomes digest
Lysosomes are
Lysosomes
In 2009, Marco Sardiello and co-workers discovered that the synthesis of most lysosomal enzymes and membrane proteins is controlled by transcription factor EB ([[TFEB]]), which promotes the transcription of [[nuclear gene]]s.<ref name = "Underwood_2018">{{cite journal|title=When the brain's waste disposal system fails |journal=Knowable Magazine | vauthors = Underwood E |doi=10.1146/knowable-121118-1 |url=https://www.knowablemagazine.org/article/living-world/2018/when-brains-waste-disposal-system-fails|year=2018 |s2cid=187669426 |doi-access=free }}</ref><ref name="pmid19556463">{{cite journal | vauthors = Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A | display-authors = 6 | title = A gene network regulating lysosomal biogenesis and function | journal = Science | volume = 325 | issue = 5939 | pages = 473–477 | date = July 2009 | pmid = 19556463 | doi = 10.1126/science.1174447 | s2cid = 20353685 | bibcode = 2009Sci...325..473S | doi-access = free }}</ref> [[Mutation]]s in the genes for these enzymes are responsible for more than 50 different human [[genetic disorder]]s
==Etymology and pronunciation==
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They succeeded in detecting the enzyme activity from the [[microsome|microsomal]] fraction. This was the crucial step in the serendipitous discovery of lysosomes. To estimate this enzyme activity, they used that of the standardized enzyme [[acid 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."<ref>{{cite journal |author= Susana Castro-Obregon|year= 2010 |title= The Discovery of Lysosomes and Autophagy |url= http://www.nature.com/scitable/topicpage/the-discovery-of-lysosomes-and-autophagy-14199828|journal= Nature Education |volume=3 |issue= 9 | pages=49 }}</ref>
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.<ref>{{cite journal | vauthors = de Duve C | title = The lysosome turns fifty | journal = Nature Cell Biology | volume = 7 | issue = 9 | pages = 847–849 | date = September 2005 | pmid = 16136179 | doi = 10.1038/ncb0905-847 | s2cid = 30307451 }}</ref> The same year, [[Alex B. Novikoff]] from the [[University of Vermont]] visited de Duve's laboratory, and successfully obtained the first [[electron microscope|electron micrographs]] of the new organelle. Using a staining method for acid phosphatase, de Duve and Novikoff confirmed the location of the [[hydrolase|hydrolytic enzymes]] of lysosomes using [[light microscope|light]] and electron microscopic studies.<ref>{{cite journal | vauthors = Novikoff AB, Beaufay H, De Duve C | title = Electron microscopy of lysosomerich fractions from rat liver | journal = The Journal of Biophysical and Biochemical Cytology | volume = 2 | issue = 4 Suppl | pages = 179–184 | date = July 1956 | pmid = 13357540 | pmc = 2229688 | doi = 10.1083/jcb.2.4.179 }}</ref><ref>{{cite journal | vauthors = Klionsky DJ | title = Autophagy revisited: a conversation with Christian de Duve | journal = Autophagy | volume = 4 | issue = 6 | pages = 740–743 | date = August 2008 | pmid = 18567941 | doi = 10.4161/auto.6398 | doi-access =
Originally, De Duve had termed the organelles the "suicide bags" or "suicide sacs" of the cells, for their hypothesized role in [[apoptosis]].<ref>Hayashi, Teru, and others. "Subcellular Particles." ''Subcellular Particles.'', 1959.</ref> However, it has since been concluded that they only play a minor role in [[cell death]].<ref>{{cite journal | vauthors = Turk B, Turk V | title = Lysosomes as "suicide bags" in cell death: myth or reality? | journal = The Journal of Biological Chemistry | volume = 284 | issue = 33 | pages = 21783–21787 | date = August 2009 | pmid = 19473965 | pmc = 2755904 | doi = 10.1074/jbc.R109.023820 | doi-access = free }}</ref>
== Function and structure ==
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[[File:Endocytic pathway of animal cells showing EGF receptors, transferrin receptors and mannose-6-phosphate receptors.jpg|alt=This is crucial for many disease pathways|thumb|The lysosome is shown in purple, as an endpoint in endocytotic 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, in [[endocytosis]] (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 from [[endosomes]].<ref name=Alberts>{{cite book| vauthors = Alberts B | title = Molecular biology of the cell|year=2002|publisher=Garland Science|location=New York|isbn=978-0-8153-3218-3|edition=4th|display-authors=etal}}</ref><ref name="endo18">{{cite journal | vauthors = Falcone S, Cocucci E, Podini P, Kirchhausen T, Clementi E, Meldolesi J | title = Macropinocytosis: regulated coordination of endocytic and exocytic membrane traffic events | journal = Journal of Cell Science | volume = 119 | issue = Pt 22 | pages = 4758–4769 | date = November 2006 | pmid = 17077125 | doi = 10.1242/jcs.03238 | doi-access =
The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes are transcribed in the [[Cell nucleus|nucleus]] in a process that is controlled by transcription factor EB ([[TFEB]]).<ref name="pmid19556463"
Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with a [[Endosome#Types|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.<ref name=Lodish /> 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.<ref name=Alberts />
== Pathogen entry ==
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 endocytotic pathways such as [[pinocytosis]] 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
==Clinical significance==
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[[Metachromatic leukodystrophy]] is another lysosomal storage disease that also affects [[sphingolipid metabolism]].
Dysfunctional lysosome activity is also heavily implicated in the biology of [[Ageing|aging]], and age-related diseases such as Alzheimer's, Parkinson's, and cardiovascular disease.<ref
== Different enzymes present in Lysosomes ==
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===Lysosomotropism===
Weak [[Base (chemistry)|bases]] with [[Lipophilicity|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 [[wikt:lysosomotropism|lysosomotropism]],<ref>{{cite journal | vauthors = de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F | title = Commentary. Lysosomotropic agents | journal = Biochemical Pharmacology | volume = 23 | issue = 18 | pages = 2495–2531 | date = September 1974 | pmid = 4606365 | doi = 10.1016/0006-2952(74)90174-9 }}</ref> "acid trapping" or "proton pump" effect.<ref>{{cite
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 as [[haloperidol]],<ref>{{cite journal | vauthors = Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter CH, Zöchling R, Boissl KW, Leblhuber F, Riederer P | display-authors = 6 | title = Persistence of haloperidol in human brain tissue | journal = The American Journal of Psychiatry | volume = 156 | issue = 6 | pages = 885–890 | date = June 1999 | pmid = 10360127 | doi = 10.1176/ajp.156.6.885 | s2cid = 7258546 }}</ref> [[levomepromazine]],<ref>{{cite journal | vauthors = Kornhuber J, Weigmann H, Röhrich J, Wiltfang J, Bleich S, Meineke I, Zöchling R, Härtter S, Riederer P, Hiemke C | display-authors = 6 | title = Region specific distribution of levomepromazine in the human brain | journal = Journal of Neural Transmission | volume = 113 | issue = 3 | pages = 387–397 | date = March 2006 | pmid = 15997416 | doi = 10.1007/s00702-005-0331-3 | s2cid = 24735371 }}</ref> and [[amantadine]].<ref>{{cite journal | vauthors = Kornhuber J, Quack G, Danysz W, Jellinger K, Danielczyk W, Gsell W, Riederer P | title = Therapeutic brain concentration of the NMDA receptor antagonist amantadine | journal = Neuropharmacology | volume = 34 | issue = 7 | pages = 713–721 | date = July 1995 | pmid = 8532138 | doi = 10.1016/0028-3908(95)00056-c | s2cid = 25784783 }}</ref> 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.<ref>{{cite journal | vauthors = Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E | title = Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 2 | pages = 219–237 | date = January 2008 | pmid = 18027916 | doi = 10.1021/jm070524a | citeseerx = 10.1.1.324.8854 }}</ref><ref>{{cite journal | vauthors = Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer TW, Spitzer GM, Liedl KR, Gulbins E, Tripal P | display-authors = 6 | title = Identification of novel functional inhibitors of acid sphingomyelinase | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23852 | year = 2011 | pmid = 21909365 | pmc = 3166082 | doi = 10.1371/journal.pone.0023852 | veditors = Riezman H | doi-access = free | bibcode = 2011PLoSO...623852K }}</ref> Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)<ref>{{cite journal | vauthors = Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, Groemer TW, Gulbins E | display-authors = 6 | title = Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications | journal = Cellular Physiology and Biochemistry | volume = 26 | issue = 1 | pages = 9–20 | year = 2010 | pmid = 20502000 | doi = 10.1159/000315101 | doi-access =
[[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 and [[Calcium channel opener|calcium release]] from acidic calcium stores.<ref>{{cite journal | vauthors = Fois G, Hobi N, Felder E, Ziegler A, Miklavc P, Walther P, Radermacher P, Haller T, Dietl P | display-authors = 6 | title = A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca²⁺ release from acidic Ca²⁺ stores | journal = Cell Calcium | volume = 58 | issue = 6 | pages = 628–637 | date = December 2015 | pmid = 26560688 | doi = 10.1016/j.ceca.2015.10.002 }}</ref> Presumably for this reason, [[Ambroxol]] was also found to improve cellular function in some disease of lysosomal origin such as [[Parkinson's disease|Parkinson]]'s or [[lysosomal storage disease]].<ref>{{cite journal | vauthors = Albin RL, Dauer WT | title = Magic shotgun for Parkinson's disease? | journal = Brain | volume = 137 | issue = Pt 5 | pages = 1274–1275 | date = May 2014 | pmid = 24771397 | doi = 10.1093/brain/awu076 | doi-access = free }}</ref><ref>{{cite journal | vauthors = McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH | display-authors = 6 | title = Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells | journal = Brain | volume = 137 | issue = Pt 5 | pages = 1481–1495 | date = May 2014 | pmid = 24574503 | pmc = 3999713 | doi = 10.1093/brain/awu020 }}</ref>
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[[Category:Vesicles]]
[[Category:Cell anatomy]]
[[Category:Eukaryotic cell anatomy]]
[[Category:Organelles]]
[[Category:Lysosomal storage diseases]]
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