Lysosome: Difference between revisions

{{Distinguish|Lysozyme|lectins}}

A '''lysosome''' ({{IPAc-en|ˈ|l|aɪ|s|ə|ˌ|s|oʊ|m}}) is a single [[membrane-bound organelle]] found in many<!--Human red blood cells and some other specialized cells don't have lysosomes--> animal [[Cell (biology)|cell]]s.<ref>{{cite journal |vauthors=Wu Y, Huang P, Dong XP |title=Lysosomal Calcium Channels in Autophagy and Cancer |journal=Cancers |volume=13 |issue=6 |date=March 2021 |page=1299 |pmid=33803964 |pmc=8001254 |doi=10.3390/cancers13061299 |doi-access=free |url=}}</ref><ref>By convention similar cells in plants are called [[vacuoles]], see {{Section link||Controversy in botany}}</ref> They are spherical [[Vesicle (biology and chemistry)|vesicles]] that contain [[Hydrolysis|hydrolytic]] [[enzyme]]s that can break downdigest many kinds of [[biomolecule]]s. A lysosome has a specific composition, of both its [[membrane protein]]s, and its [[lumen (anatomy)|lumenal]] proteins. The lumen's pH (~4.5–5.0)<ref>{{cite journal | vauthors = Ohkuma S, Poole B | title = Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 75 | issue = 7 | pages = 3327–3331 | date = July 1978 | pmid = 28524 | pmc = 392768 | doi = 10.1073/pnas.75.7.3327 | doi-access = free | bibcode = 1978PNAS...75.3327O }}</ref> is optimal for the enzymes involved in hydrolysis, analogous to the activity of the [[stomach]]. Besides degradation of polymers, the lysosome is involved in various cell processes, includingof secretion, [[plasma membrane]] repair, [[apoptosis]], [[cell signaling]], and [[energy metabolism]].<ref>{{cite journal | vauthors = Settembre C, Fraldi A, Medina DL, Ballabio A | title = Signals from the lysosome: a control centre for cellular clearance and energy metabolism | journal = Nature Reviews. Molecular Cell Biology | volume = 14 | issue = 5 | pages = 283–296 | date = May 2013 | pmid = 23609508 | pmc = 4387238 | doi = 10.1038/nrm3565 }}</ref>

[[File:Lysosomes Digestion.svg|thumb|Lysosomes digest materials taken into the cell and recycle intracellular materialsmaterial. 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 picture 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.<ref>{{cite book | vauthors = Holtzclaw FW, etal | title = AP* Biology: to Accompany Biology | edition = 8th AP | publisher = Pearson Benjamin Cummings | date = 2008 }}</ref>]]

Lysosomes are termed to be degradative organelles that act as the waste disposal system of the cell by digesting used materials in the [[cytoplasm]], from both inside and outside the cell. Material from outside the cell is taken up through [[endocytosis]], while material from the inside of the cell is digested through [[autophagy]].<ref name = "Underwood_2018" /> The sizes of the organelles vary greatly—the larger ones can be more than 10 times the size of the smaller ones.<ref>{{cite book| veditors = Zaftig P | title = Lysosomes | chapter = History and Morphology of Lysosome | vauthors = Lüllmznn-Rauch R | date = 2005 | publisher = Landes Bioscience/Eurekah.com | location=Georgetown, Tex. | isbn = 978-0-387-28957-1 | edition = Online-Ausg. 1 | pages = 1–16 | chapter-url = https://books.google.com/books?id=mTgNUPS5tcUC}}</ref> They were discovered and named by Belgian biologist [[Christian de Duve]], who eventually received the [[Nobel Prize in Physiology or Medicine]] in 1974.

Lysosomes are known to contain more than 60 different enzymes, and have more than 50 membrane proteins.<ref>{{cite journal | vauthors = Xu H, Ren D | title = Lysosomal physiology | journal = Annual Review of Physiology | volume = 77 | issue = 1 | pages = 57–80 | date = 2015 | pmid = 25668017 | pmc = 4524569 | doi = 10.1146/annurev-physiol-021014-071649 }}</ref><ref>{{cite web|title=Lysosomal Enzymes|url=https://www.rndsystems.com/research-area/lysosomal-enzymes|website=www.rndsystems.com|publisher=R&D Systems|access-date=4 October 2016}}</ref> Enzymes of the lysosomes are synthesized in the [[rough endoplasmic reticulum]] and exported to the [[Golgi apparatus]] upon recruitment by a complex composed of [[CLN6]] and [[CLN8]] proteins.<ref name="di Ronza, A. 2018">{{cite journal | vauthors = di Ronza A, Bajaj L, Sharma J, Sanagasetti D, Lotfi P, Adamski CJ, Collette J, Palmieri M, Amawi A, Popp L, Chang KT, Meschini MC, Leung HE, Segatori L, Simonati A, Sifers RN, Santorelli FM, Sardiello M | display-authors = 6 | title = CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis | journal = Nature Cell Biology | volume = 20 | issue = 12 | pages = 1370–1377 | date = December 2018 | pmid = 30397314 | pmc = 6277210 | doi = 10.1038/s41556-018-0228-7 }}</ref><ref name="pmid32597833">{{cite journal | vauthors = Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, Roman D, Collette JR, Booth C, Chang KT, Sifers RN, Jung SY, Weimer JM, Chen R, Schekman RW, Sardiello M | display-authors = 6 | title = A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer | journal = The Journal of Clinical Investigation | volume = 130 | issue = 8 | pages = 4118–4132 | date = August 2020 | pmid = 32597833 | pmc = 7410054 | doi = 10.1172/JCI130955 | doi-access = free }}</ref> The enzymes are traffickedtransported from the [[Golgi apparatus]] to lysosomes in small vesicles, which fuse with larger acidic vesicles. Enzymes destined for a lysosome are specifically tagged with the molecule [[mannose 6-phosphate]], so that they are properly sorted into acidified vesicles.<ref>{{cite journal | vauthors = Saftig P, Klumperman J | title = Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 9 | pages = 623–635 | date = September 2009 | pmid = 19672277 | doi = 10.1038/nrm2745 | s2cid = 24493663 }}</ref><ref>{{cite journal | vauthors = Samie MA, Xu H | title = Lysosomal exocytosis and lipid storage disorders | journal = Journal of Lipid Research | volume = 55 | issue = 6 | pages = 995–1009 | date = June 2014 | pmid = 24668941 | pmc = 4031951 | doi = 10.1194/jlr.R046896 |doi-access=free }}</ref>

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, which are collectively known as [[lysosomal storage disease]]s. These diseases result fromin an accumulation of specific [[Substrate (chemistry)|substrates]], due to the inability to break them down. These genetic defects are related to several [[neurodegenerative disorders]], cancers, [[cardiovascular diseases]], and [[ageing|aging-related]] diseases.<ref name="platt">{{cite journal | vauthors = Platt FM, Boland B, van der Spoel AC | title = The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction | journal = The Journal of Cell Biology | volume = 199 | issue = 5 | pages = 723–734 | date = November 2012 | pmid = 23185029 | pmc = 3514785 | doi = 10.1083/jcb.201208152 }}</ref><ref>{{cite journal | vauthors = He LQ, Lu JH, Yue ZY | title = Autophagy in ageing and ageing-associated diseases | journal = Acta Pharmacologica Sinica | volume = 34 | issue = 5 | pages = 605–611 | date = May 2013 | pmid = 23416930 | pmc = 3647216 | doi = 10.1038/aps.2012.188 }}</ref><ref name="The crucial impact of lysosomes in">{{cite journal | vauthors = Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C | title = The crucial impact of lysosomes in aging and longevity | journal = Ageing Research Reviews | volume = 32 | pages = 2–12 | date = December 2016 | pmid = 27125853 | pmc = 5081277 | doi = 10.1016/j.arr.2016.04.009 | series = Lysosomes in Aging }}</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 = free }}</ref> de Duve won the [[Nobel Prize in Physiology or Medicine]] in 1974 for this discovery.

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 = free }}</ref>

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">{{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 }}</ref> mRNA transcripts exit the nucleus into the cytosol, where they are translated by [[ribosomes]]. The nascent peptide chains are [[Protein targeting#Protein translocation|translocated]] into the rough [[endoplasmic reticulum]], where they are modified. Lysosomal soluble proteins exit the endoplasmic reticulum via [[COPII]]-coated vesicles after recruitment by the [[EGRESS complex]] ('''E'''R-to-'''G'''olgi '''r'''elaying of '''e'''nzymes of the ly'''s'''osomal '''s'''ystem), which is composed of [[CLN6]] and [[CLN8]] proteins.<ref name="di Ronza, A. 2018">{{cite journal | vauthors = di Ronza A, Bajaj L, Sharma J, Sanagasetti D, Lotfi P, Adamski CJ, Collette J, Palmieri M, Amawi A, Popp L, Chang KT, Meschini MC, Leung HE, Segatori L, Simonati A, Sifers RN, Santorelli FM, Sardiello M | display-authors = 6 | title = CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis | journal = Nature Cell Biology | volume = 20 | issue = 12 | pages = 1370–1377 | date = December 2018 | pmid = 30397314 | pmc = 6277210 | doi = 10.1038/s41556-018-0228-7 }}</ref><ref name="pmid32597833">{{cite journal | vauthors = Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, Roman D, Collette JR, Booth C, Chang KT, Sifers RN, Jung SY, Weimer JM, Chen R, Schekman RW, Sardiello M | display-authors = 6 | title = A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer | journal = The Journal of Clinical Investigation | volume = 130 | issue = 8 | pages = 4118–4132 | date = August 2020 | pmid = 32597833 | pmc = 7410054 | doi = 10.1172/JCI130955 | doi-access = free }}</ref> COPII vesicles then deliver lysosomal enzymes to the [[Golgi apparatus]], where a specific lysosomal tag, [[mannose 6-phosphate]], is added to the peptides. The presence of these tags allow for binding to [[mannose 6-phosphate receptor]]s in the Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for the lysosomal system.<ref name=Lodish>{{cite book| vauthors = Lodish H |title=Molecular cell biology|year=2000|publisher=Scientific American Books|location=New York|isbn=978-0-7167-3136-8|edition=4th|display-authors=etal|url-access=registration|url=https://archive.org/details/molecularcellbio00lodi}}</ref>

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 Lysosomallysosomal activity results in an increase in viral infectivity, including HIV.<ref name="Wei, Bangdong L. 2005">{{cite journal | vauthors = Wei BL, Denton PW, O'Neill E, Luo T, Foster JL, Garcia JV | title = Inhibition of lysosome and proteasome function enhances human immunodeficiency virus type 1 infection | journal = Journal of Virology | volume = 79 | issue = 9 | pages = 5705–5712 | date = May 2005 | pmid = 15827185 | pmc = 1082736 | doi = 10.1128/jvi.79.9.5705-5712.2005 }}</ref> In addition, [[AB5 toxin|AB₅]] toxins such as [[Cholera toxin|cholera]] hijack the endosomal pathway while evading lysosomal degradation.<ref name="Wei, Bangdong L. 2005"/>

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>{{cite journal | vauthors name= Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C | title = "The crucial impact of lysosomes in aging and longevity | journal = Ageing Research Reviews | volume = 32 | pages = 2–12 | date = December 2016 | pmid = 27125853 | pmc = 5081277 | doi = 10.1016/j.arr.2016.04.009 | series = Lysosomes in Aging }}<"/ref><ref>{{cite journal | vauthors = Finkbeiner S | title = The Autophagy Lysosomal Pathway and Neurodegeneration | journal = Cold Spring Harbor Perspectives in Biology | volume = 12 | issue = 3 | pages = a033993 | date = March 2020 | pmid = 30936119 | pmc = 6773515 | doi = 10.1101/cshperspect.a033993 }}</ref>

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 journalbook | vauthors = Traganos F, Darzynkiewicz Z | title = Lysosomal proton pump activity: supravital cell staining with acridine orange differentiates leukocyte subpopulations | journalchapter = Chapter 12 Lysosomal Proton Pump Activity: Supravital Cell Staining with Acridine Orange Differentiates Leukocyte Subpopulations | series = Methods in Cell Biology | volume = 41 | pages = 185–194 | year = 1994 | pmid = 7532261 | doi = 10.1016/S0091-679X(08)61717-3 | isbn = 978-0-12-564142-5 }}</ref> The amount of accumulation of lysosomotropic compounds may be estimated using a cell-based mathematical model.<ref>{{cite journal | vauthors = Trapp S, Rosania GR, Horobin RW, Kornhuber J | title = Quantitative modeling of selective lysosomal targeting for drug design | journal = European Biophysics Journal | volume = 37 | issue = 8 | pages = 1317–1328 | date = October 2008 | pmid = 18504571 | pmc = 2711917 | doi = 10.1007/s00249-008-0338-4 }}</ref>

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 = free }}</ref> and include for example [[fluoxetine]], [[sertraline]], or [[amitriptyline]].