Lysosome: Difference between revisions

{{Distinguish|Lysozyme|lectins}}

A '''ysosomelysosome''' ({{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 = 3327–313327–3331 | date = July 1978 | pmid = 28524 | pmc = 392768 | doi = 10.1073/pnas.75.7.3327 | doi-access = free | bibcode = 1978PNAS...75.3327O | doi-access = free }}</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 = 283–96283–296 | 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>]]

ysosomesLysosomes are 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>{{cite journal|title=Whenname the brain's waste disposal system fails |journal=Knowable Magazine"Underwood_2018" |last=Underwood |first=Emily |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 }}</ref> 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| editor-last1veditors = Zaftig | editor-first1 = PaulP | title = Lysosomes | chapter = History and Morphology of Lysosome | first1 = Renate | last1vauthors = Lüllmznn-Rauch | name-list-style = vancR | 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 = JThe Journal of ClinClinical InvestInvestigation | volume = 130 | issue = 8 | pages = 4118–4132 | date = JunAugust 2020 | pmid = 32597833 | pmc = 7410054 | doi = 10.1172/JCI130955 | pmc = 7410054 | 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 = 623–35623–635 | 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 |last vauthors = Underwood |first=EmilyE |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 = 473–7473–477 | date = JulJuly 2009 | pmid = 19556463 | doi = 10.1126/science.1174447 | s2cid = 20353685 | bibcode = 2009Sci...325..473S | s2ciddoi-access = 20353685free }}</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 = 723–34723–734 | 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 = 605–11605–611 | date = May 2013 | pmid = 23416930 | pmc = 3647216 | doi = 10.1038/aps.2012.188 }}</ref><ref name="The crucial impact of lysosomes in">{{Citecite journal |last1 vauthors = Carmona-Gutierrez|first1=Didac|last2= D, Hughes|first2=Adam L.|last3=AL, Madeo|first3=Frank|last4= F, Ruckenstuhl C |first4=Christoph|date=2016-12-01| title = The crucial impact of lysosomes in aging and longevity | journal = Ageing Research Reviews|series=Lysosomes in Aging| volume = 32 | pages = 2–12 | date = December 2016 | pmid = 27125853 | pmc = 5081277 | doi = 10.1016/j.arr.2016.04.009|pmid=27125853|pmc=5081277|issn=1568-1637 }}</ref>

The word ''lysosome'' ({{IPAc-en|ˈ|l|aɪ|s|oʊ|s|oʊ|m}}, {{IPAc-en|ˈ|l|aɪ|z|ə|z|oʊ|m}}) is [[New Neo-Latin]] that uses the [[classical compound|combining forms]] ''lyso-'' (referring to [[wikt:lysis#Noun|lysis]] and derived from the Latin ''[[wikt:lysis#Latin|lysis]]'', meaning "to loosen", via Ancient Greek λύσις [lúsis]), and ''[[wikt:-some#Etymology 3|-some]]'', from ''[[soma (biology)|soma]]'', "body", yielding "body that lyses" or "lytic body". The adjectival form is ''lysosomal''. The forms ''*lyosome'' and ''*lyosomal'' are much rarer; they use the ''[[wikt:lyo-#Prefix|lyo-]]'' form of the prefix but are often treated by readers and editors as mere unthinking replications of [[typographical error|typos]], which has no doubt been true as often as not.

In 1955 , discovered by “ [[Christian de Duve]],” the chairman ofat the Laboratory of Physiological Chemistry at the [[Université Catholique de Louvain|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 focused 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. Therefore, they tried a more arduous procedure of [[cell fractionation]], by which cellular components are separated based on their sizes using [[centrifugation]].

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 = 847–9847–849 | 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 = 179–84179–184 | 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 = 740–3740–743 | 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.

The size of lysosomes varies from 0.1 [[micrometre|μm]] to 1.2 [[micrometre|μm]].<ref>{{cite book | lastvauthors = Kuehnel | first=W | name-list-style = vanc | title=Color Atlas of Cytology, Histology, & Microscopic Anatomy | publisher=Thieme | year=2003 | edition=4th | pages=34 | isbn=978-1-58890-175-0 }}</ref> With a [[pH]] ranging from ~4.5–5.0, the interior of the lysosomes is acidic compared to the slightly basic [[cytosol]] (pH 7.2). The lysosomal membrane protects the cytosol, and therefore the rest of the [[cell (biology)|cell]], from the [[degradative enzyme]]s 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 destroyed in case there is leakage of the hydrolytic enzymes from the lysosome.

The lysosome maintains its pH differential by pumping in [[proton]]s (H⁺ ions) from the cytosol across the [[Cell membrane|membrane]] via [[proton pump]]s and [[chloride channel|chloride ion channel]]s. [[V-ATPase|Vacuolar-ATPase]]s are responsible for transport of protons, while the counter transport of chloride ions is performed by [[CLCN7|ClC-7]] Cl⁻/H⁺ antiporter. In this way a steady acidic environment is maintained.<ref name="Lysosomal acidification mechanisms">{{cite journal | vauthors = Mindell JA |year=2012| title = Lysosomal acidification mechanisms | journal = Annual Review of Physiology | volume = 74 | issue = 1 | pages = 69–86 | year = 2012 | pmid = 22335796 | doi = 10.1146/annurev-physiol-012110-142317 |pmid=22335796| url = https://zenodo.org/record/894445 }}</ref><ref>{{cite journal | vauthors = Ishida Y, Nayak S, Mindell JA, Grabe M | title = A model of lysosomal pH regulation | journal = The Journal of General Physiology | volume = 141 | issue = 6 | pages = 705–20705–720 | date = June 2013 | pmid = 23712550 | pmc = 3664703 | doi = 10.1085/jgp.201210930 }}</ref>

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|last=Alberts|first=Bruce |vauthors name-list-style= =Alberts vancB | 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 = 4758–694758–4769 | 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 | title = A gene network regulating lysosomal biogenesis and function | journal = Science | volume = 325 | issue = 5939 | pages = 473–7 | date = Jul 2009 | pmid = 19556463 | doi = 10.1126/science.1174447 | bibcode = 2009Sci...325..473S | s2cid = 20353685 }}</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 | 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 | title = A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer | journal = J Clin Invest | volume = 130| issue = 8| pages = 4118–4132| date = Jun 2020 | pmid = 32597833 | doi = 10.1172/JCI130955 | pmc = 7410054 | 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|last vauthors = Lodish|first=Harvey|name-list-style=vanc 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 = 5705–125705–5712 | 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"/>

Lysosomes are involved in a group of genetically inherited deficiencies, or mutations called [[lysosomal 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 an [[acid 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.<ref name=platt/> This results in abnormal signaling pathways, [[calcium homeostasis]], [[Lipid synthesis|lipid biosynthesis]] and degradation and intracellular trafficking, ultimately leading to pathogenetic disorders. The organs most affected are [[Central nervous system|brain]], [[viscera]], bone and [[cartilage]].<ref>{{cite journal | vauthors = Schultz ML, Tecedor L, Chang M, Davidson BL | title = Clarifying lysosomal storage diseases | journal = Trends in Neurosciences | volume = 34 | issue = 8 | pages = 401–10401–410 | date = August 2011 | pmid = 21723623 | pmc = 3153126 | doi = 10.1016/j.tins.2011.05.006 }}</ref><ref>{{cite journal | vauthors = Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A | title = Autophagy in lysosomal storage disorders | journal = Autophagy | volume = 8 | issue = 5 | pages = 719–30719–730 | date = May 2012 | pmid = 22647656 | pmc = 3378416 | doi = 10.4161/auto.19469 }}</ref>

There is no direct medical treatment to cure LSDs.<ref>.{{cite journal | vauthors = Parenti G, Pignata C, Vajro P, Salerno M | title = New strategies for the treatment of lysosomal storage diseases (review) | journal = International Journal of Molecular Medicine | volume = 31 | issue = 1 | pages = 11–20 | date = January 2013 | pmid = 23165354 | doi = 10.3892/ijmm.2012.1187 | doi-access = free }}</ref> The most common LSD is [[Gaucher's disease]], which is due to deficiency of the enzyme [[glucocerebrosidase]]. Consequently, the enzyme substrate, the fatty acid [[glucosylceramide]] accumulates, particularly in [[white 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.<ref>{{cite journal | vauthors = Rosenbloom BE, Weinreb NJ | title = Gaucher disease: a comprehensive review | journal = Critical Reviews in Oncogenesis | volume = 18 | issue = 3 | pages = 163–75163–175 | year = 2013 | pmid = 23510062 | doi = 10.1615/CritRevOncog.2013006060 }}</ref><ref>{{cite journal | vauthors = Sidransky E | title = Gaucher disease: insights from a rare Mendelian disorder | journal = Discovery Medicine | volume = 14 | issue = 77 | pages = 273–81273–281 | date = October 2012 | pmid = 23114583 | pmc = 4141347 }}</ref> As of 2017, [[enzyme replacement therapy]] is available for treating 8 of the 50-60 known LDs.<ref name="Solomon">{{cite journal | vauthors = Solomon M, Muro S | title = Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives | journal = Advanced Drug Delivery Reviews | volume = 118 | pages = 109–134 | date = September 2017 | pmid = 28502768 | pmc = 5828774 | doi = 10.1016/j.addr.2017.05.004 }}</ref>

The most severe and rarely found, lysosomal storage disease is [[inclusion cell disease]].<ref name="Alberts2004">{{cite book |last1 vauthors = Alberts |first1=BruceB |title=Molecular biologyBiology of the cellCell |publisher=Garland Science |isbn=978-0815340720 |page=744 |edition=4th|year=2002 }}</ref>

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|last1=Carmona-Gutierrez|first1=Didac|last2=Hughes|first2=Adam L.|last3=Madeo|first3=Frank|last4=Ruckenstuhl|first4=Christoph|date=2016-12-01|titlename="The crucial impact of lysosomes in aging and longevity|journal=Ageing Research Reviews|series=Lysosomes in Aging|volume=32|pages=2–12|doi=10.1016"/j.arr.2016.04.009|pmid=27125853|pmc=5081277|issn=1568-1637}}</ref><ref>{{Citecite journal |last vauthors = Finkbeiner S |first=Steven|date=2019-04-01| title = The Autophagy Lysosomal Pathway and Neurodegeneration |url=http://cshperspectives.cshlp.org/content/early/2019/04/01/cshperspect.a033993| journal = Cold Spring Harbor Perspectives in Biology | volume = 12 | issue = 3 |language=en| pages = a033993 | date = March 2020 | pmid = 30936119 | pmc = 6773515 | doi = 10.1101/cshperspect.a033993|issn=1943-0264|pmid=30936119|pmc=6773515 }}</ref>

== Different enzymes present in Lysosomes <ref>{{Cite book | vauthors = Kumar P, Mina U |title=Life Sciences : Fundamentals and practice.|last=Pranav Kumar.|date=2013|publisher=Pathfinder Academy|others=Mina, Usha.|isbn=978-81-906427-0-5|edition=3rd|location=New Delhi|oclc=857764171}}</ref> ==

|Bacterial cell walls and mucopolysaccharides

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 = 2495–5312495–2531 | 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 | year = 1994 | 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 Biol.Biology | volume = 41 | pages = 185–94185–194 | 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 = 1317–281317–1328 | 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 = 885–90885–890 | date = June 1999 | pmid = 10360127 | doi = 10.1176/ajp.156.6.885 | s2cid = 7258546 | url = https://semanticscholar.org/paper/ae9d21e67f7a28ba8c030826cbc91ab4d4be1a26 }}</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 = 387–97387–397 | 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 = 713–21713–721 | 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 = 219–37219–237 | 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 | bibcodeveditors = 2011PLoSO...623852KRiezman | editor1-last = RiezmanH | editor1doi-firstaccess = Howardfree | doi-accessbibcode = free2011PLoSO...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]].

[[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 = 628–37628–637 | 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 = 1274–51274–1275 | 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 = 1481–951481–1495 | date = May 2014 | pmid = 24574503 | pmc = 3999713 | doi = 10.1093/brain/awu020 | url = }}</ref>

Impaired lysosome function is prominent in systemic lupus erythematosus preventing macrophages and monocytes from degrading neutrophil extracellular traps<ref>{{cite journal | vauthors = Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A | display-authors = 6 | title = Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 21 | pages = 9813–89813–9818 | date = May 2010 | pmid = 20439745 | pmc = 2906830 | doi = 10.1073/pnas.0909927107 | doi-access = free | bibcode = 2010PNAS..107.9813H | doi-access = free }}</ref> and immune complexes.<ref name=":0">{{cite journal | vauthors = Monteith AJ, Kang S, Scott E, Hillman K, Rajfur Z, Jacobson K, Costello MJ, Vilen BJ | display-authors = 6 | title = Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 15 | pages = E2142–51E2142–E2151 | date = April 2016 | pmid = 27035940 | pmc = 4839468 | doi = 10.1073/pnas.1513943113 | bibcodedoi-access = 2016PNAS..113E2142Mfree | doi-accessbibcode = free2016PNAS..113E2142M }}</ref><ref>{{cite journal | vauthors = Kavai M, Szegedi G | title = Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus | journal = Autoimmunity Reviews | volume = 6 | issue = 7 | pages = 497–502 | date = August 2007 | pmid = 17643939 | doi = 10.1016/j.autrev.2007.01.017 }}</ref><ref name="pmid3787186">{{cite journal | vauthors = Kávai M, Csipö I, Sonkoly I, Csongor J, Szegedi GY | title = Defective immune complex degradation by monocytes in patients with systemic lupus erythematosus | journal = Scandinavian Journal of Immunology | volume = 24 | issue = 5 | pages = 527–32527–532 | date = November 1986 | pmid = 3787186 | doi = 10.1111/j.1365-3083.1986.tb02167.x | s2cid = 23685272 }}</ref> The failure to degrade internalized immune complexes stems from chronic mTORC2 activity, which impairs lysosome acidification.<ref>{{cite journal | vauthors = Monteith AJ, Vincent HA, Kang S, Li P, Claiborne TM, Rajfur Z, Jacobson K, Moorman NJ, Vilen BJ | display-authors = 6 | title = mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a | journal = Journal of Immunology | volume = 201 | issue = 2 | pages = 371–382 | date = July 2018 | pmid = 29866702 | pmc = 6039264 | doi = 10.4049/jimmunol.1701712 }}</ref> 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.<ref name=":0" /><ref>{{cite journal | vauthors = Kang S, Rogers JL, Monteith AJ, Jiang C, Schmitz J, Clarke SH, Tarrant TK, Truong YK, Diaz M, Fedoriw Y, Vilen BJ | display-authors = 6 | title = Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus | journal = Journal of Immunology | volume = 196 | issue = 10 | pages = 4030–94030–4039 | date = May 2016 | pmid = 27059595 | pmc = 4868781 | doi = 10.4049/jimmunol.1500418 }}</ref><ref>{{cite journal | vauthors = Kang S, Fedoriw Y, Brenneman EK, Truong YK, Kikly K, Vilen BJ | title = BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis | journal = Journal of Immunology | volume = 198 | issue = 7 | pages = 2602–2611 | date = April 2017 | pmid = 28235864 | pmc = 5360485 | doi = 10.4049/jimmunol.1600281 }}</ref>

By scientific convention, the term lysosome is applied to these vesicular organelles only in animals, and the term [[vacuole]] 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.<ref>{{cite journal | vauthors = Marty F | title = Plant vacuoles | journal = The Plant Cell | volume = 11 | issue = 4 | pages = 587–600 | date = April 1999 | pmid = 10213780 | pmc = 144210 | doi = 10.2307/3870886 | jstor = 3870886 }}</ref><ref>{{cite journal | vauthors = Samaj J, Read ND, Volkmann D, Menzel D, Baluska F | title = The endocytic network in plants | journal = Trends in Cell Biology | volume = 15 | issue = 8 | pages = 425–33425–433 | date = August 2005 | pmid = 16006126 | doi = 10.1016/j.tcb.2005.06.006 }}</ref> Some vacuoles contain their own hydrolytic enzymes and perform the classic lysosomal activity, which is autophagy.<ref>{{cite journal|last vauthors = Matile|first= P |title=Biochemistry and Function of Vacuoles|journal=Annual Review of Plant Physiology|year=1978|volume=29|issue=1|pages=193–213|doi=10.1146/annurev.pp.29.060178.001205}}</ref><ref>{{cite journal | vauthors = Moriyasu Y, Ohsumi Y | title = Autophagy in Tobacco Suspension-Cultured Cells in Response to Sucrose Starvation | journal = Plant Physiology | volume = 111 | issue = 4 | pages = 1233–1241 | date = August 1996 | pmid = 12226358 | pmc = 161001 | doi = 10.1104/pp.111.4.1233 }}</ref><ref>{{cite journal | vauthors = Jiao BB, Wang JJ, Zhu XD, Zeng LJ, Li Q, He ZH | title = A novel protein RLS1 with NB-ARM domains is involved in chloroplast degradation during leaf senescence in rice | journal = Molecular Plant | volume = 5 | issue = 1 | pages = 205–17205–217 | date = January 2012 | pmid = 21980143 | doi = 10.1093/mp/ssr081 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Swanson SJ, Bethke PC, Jones RL | title = Barley aleurone cells contain two types of vacuoles. Characterization Of lytic organelles by use of fluorescent probes | journal = The Plant Cell | volume = 10 | issue = 5 | pages = 685–98685–698 | date = May 1998 | pmid = 9596630 | pmc = 144374 | doi = 10.2307/3870657 | jstor = 3870657 }}</ref> 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.<ref>{{cite book|last=Holtzman|first=Eric |vauthors name-list-style= =Holtzman vancE | title = Lysosomes|year=1989|publisher=Plenum Press|location=New York|isbn=978-0306-4-3126-5|pages=7, 15}}</ref> Vacuoles do not have catabolic activity and do not undergo [[exocytosis]] as lysosomes do.<ref>{{cite book|last=De|first=Deepesh N.vauthors |= name-list-style =De vancDN | title = Plant Cell Vacuoles: An Introduction | year = 2000 | publisher = Csiro Publishing | location = Australia | isbn =978-0-643-09944-9 | url = https://books.google.com/books?id=o5H13nnYXngC}}</ref>