|The animal cell|
A lysosome (derived from the Greek words lysis, meaning "to loosen", and soma, "body") is a membrane-bound cell organelle found in animal cells (they are absent in red blood cells). They are structurally and chemically spherical vesicles containing hydrolitic enzymes, which are capable of breaking down virtually all kinds of biomolecules, including proteins, nucleic acids, carbohydrates, lipids, and cellular debris. They are known to contain more than fifty different enzymes which are all active at an acidic environment of about pH 5. Thus they act as waste disposal system of the cell by digesting unwanted materials in the cytoplasm, both from outside of the cell and obsolete components inside the cell. For this function they are popularly referred to as "suicide bags" or "suicide sacs" of the cell. Further, lysosomes are responsible for cellular homeostasis for their involvements in secretion, plasma membrane repair, cell signalling and energy metabolism, which are related to health and diseases. Depending on their functional activity their sizes can be very different, as the biggest ones can be more than 10 times bigger than the smallest ones. They were discovered and named by Belgian biologist Christian de Duve, who eventually received the Nobel Prize in Physiology or Medicine in 1974.
Enzymes of the lysosomes are synthesised in the rough endoplasmic reticulum. The enzymes are released from Golgi apparatus in small vesicles which ultimately fuse with acidic vesicles called endosomes, thus becoming full lysosomes. In the process the enzymes are specifically tagged with mannose 6-phosphate to differentiate them from other enzymes. Lysosomes are interlinked with three intracellular processes namely phagocytosis, endocytosis and autophagy. Extracellular materials such as microorganisms taken up by phagocytosis, macromolecules by endocytosis, and unwanted cell organelles are fused with lysosomes in which they are broken down to their basic molecules. Thus lysosomes are the recycling units of a cell.
Synthesis of lysosomal enzymes are controlled by nuclear genes. Mutations in the genes for these enzymes are responsible for more than 30 different human genetic diseases, which are collectively known as lysosomal storage diseases. These diseases are due to deficiency in a single lysosomal enzyme that prevent break down of target molecules, and consequently undegraded materials accumulate within the lysosomes often giving rise to severe clinical symptoms. Further, these genetic defects are related to several neurodegenerative disorders, cancer, cardiovascular diseases, and ageing-related diseases.
Christian de Duve, then chairman of the Laboratory of Physiological Chemistry at the 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. They succeeded in detecting the enzyme activity from the microsomal fraction. This was the crucial step in the serendipitous discovery. To estimate the enzyme activity, they used that of standardised enzyme acid phosphatase, and found that the activity was quite low (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. This led to the conclusion that a membrane-like barrier limited the accessibility of the enzyme to its substrate, so that the enzymes were able to diffuse after a few days. They described the membrane-like barrier as a "saclike structure surrounded by a membrane and containing acid phosphatase." It became obvious that an unrelated enzyme from the cell fraction came from a membranous fractions which were definitely cell organelles, and in 1955 De Duve named them "lysosomes" to reflect their digestive properties. That same year, Alex B. Novikoff from the University of Vermont visited de Duve´s laboratory, and successfully obtained the first electron micrographs of the new organelle. Using a staining method for acid phosphatase, de Duve and Novikoff confirmed the location of the hydrolytic enzymes of lysosomes using light and electron microscopic studies. de Duve won the Nobel Prize in Physiology or Medicine in 1974 for this discovery.
Function and structure
Lysosomes are cellular organelles that contain acid hydrolase enzymes that break down waste materials and cellular debris. They can be described as the stomach of the cell. Lysosomes digest excess or worn-out organelles, food particles, and engulfed viruses or bacteria. The membrane around a lysosome allows the digestive enzymes to work at the pH they require. Lysosomes fuse with autophagic vacuoles (phagosomes) and dispense their enzymes into the autophagic vacuoles, digesting their contents. They are frequently nicknamed "suicide bags" or "suicide sacs" by cell biologists due to their autolysis.
The size of lysosomes varies from 0.1–1.2 μm. At pH 4.8, the interior of the lysosomes is acidic compared to the slightly basic 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. Vacuolar H+-ATPases are responsible for transport of protons, while the counter transport of chloride ions is performed by ClC-7 Cl-/H+ antiporter. In this way a steady acidic environment is maintained. 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 destroyed in case there is leakage of the hydrolytic enzymes from the lysosome.
Many components of animal cells are recycled by transferring them inside or embedded in sections of membrane. For instance, in endocytosis, a portion of the cell’s plasma membrane pinches off to form a vesicle 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.
The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes are transcribed in the nucleus. mRNA transcripts exit the nucleus into the cytosol, where they are translated by ribosomes. The nascent peptide chains are translocated into the rough endoplasmic reticulum, where they are modified. Upon exiting the endoplasmic reticulum and entering the Golgi apparatus via vesicular transport, a specific lysosomal tag, mannose 6-phosphate, is added to the peptides. The presence of these tags allow for binding to mannose 6-phosphate receptors in the Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for the lysosomal system.
Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with a 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. 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.
Lysosomes are responsible for a group of genetically inherited disorders called lysosomal storage diseases (LSD). They are a type of inborn errors of metabolism caused by malfunction of one of the enzymes. The rate of incidence is estimated to be 1 in 5,000 live 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 acidic hydrolase, while there are conditions of defects in lysosomal membrane proteins that fail to transport the enzyme, or non-enzymatic soluble lysosomal proteins. The initial effect is accumulation of specific macromolecules or monomeric compounds inside the endosomal–autophagic–lysosomal system. This results in abnormal signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking, ultimately leading to pathogenetic disorders. The organs most affected are brain, viscera, bone and cartilage. There is no direct medical treatment to cure LSDs. 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.
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" or "acid trapping". The amount of accumulation of lysosomotropic compounds may be estimated using a cell based mathematical model.
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-lifes; these properties have been found for drugs such as haloperidol, levomepromazine, and amantadine. 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 lysososomally accumulated drugs. Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase) and include for example fluoxetine, sertraline, or amitriptyline.
Controversy in botany
By scientific convention, the term lysosome is applied to those vesicular organelles only in animals, and vacuoles to plants, fungi and algae. 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. Some vacuoles contain their own hydrolytic enzymes and perform the classic lysosomal activity, which is autophagy. 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 botanist strongly argued that these vacuoles are lysosomes. 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. Vacuoles do not have catabolic activity and do not undergo exocytosis as lysosomes do.
- Settembre, Carmine; Fraldi, Alessandro; Medina, Dielo L.; Ballabio, Andrea (2013). "Signals from the lysosome: a control centre for cellular clearance and energy metabolism". Nature Reviews Molecular Cell Biology 14 (5): 283–296. doi:10.1038/nrm3565. PMID 23609508.
- Lüllmann-Rauch, Renate (2005). "History and morphology of lysosome". In Saftig, Paul. Lysosomes (Online-Ausg. ed.). Georgetown, Tex.: Landes Bioscience/Eurekah.com. pp. 1–16. ISBN 9780387289571.
- Appelqvist, H.; Waster, P.; Kagedal, K.; Ollinger, K. (2013). "The lysosome: from waste bag to potential therapeutic target". Journal of Molecular Cell Biology 5 (4): 214–226. doi:10.1093/jmcb/mjt022. PMID 23918283.
- Platt, F. M.; Boland, B.; van der Spoel, A. C. (2012). "The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction". The Journal of Cell Biology 199 (5): 723–734. doi:10.1083/jcb.201208152. PMC 3514785. PMID 23185029.
- He, Li-qiang; Lu, Jia-hong; Yue, Zhen-yu (2013). "Autophagy in ageing and ageing-associated diseases". Acta Pharmacologica Sinica 34 (5): 605–611. doi:10.1038/aps.2012.188. PMC 3647216. PMID 23416930.
- Susana Castro-Obregon (2010). "The Discovery of Lysosomes and Autophagy". Nature Education 3 (9): 49.
- De Duve, C (2005). "The lysosome turns fifty". Nature Cell Biology 7 (9): 847–9. doi:10.1038/ncb0905-847. PMID 16136179.
- Novikoff, AB; Beaufay, H; De Duve, C (1956). "Electron microscopy of lysosomerich fractions from rat liver". The Journal of biophysical and biochemical cytology 2 (4 Suppl): 179–84. doi:10.1083/jcb.2.4.179. PMC 2229688. PMID 13357540.
- Klionsky, DJ (2008). "Autophagy revisited: A conversation with Christian de Duve". Autophagy 4 (6): 740–3. doi:10.4161/auto.6398. PMID 18567941.
- Kuehnel, W (2003). Color Atlas of Cytology, Histology, & Microscopic Anatomy (4th ed.). Thieme. p. 34. ISBN 1-58890-175-0.
- Mindell, Joseph A. (2012). "Lysosomal acidification mechanisms". Annual Review of Physiology 74 (1): 69–86. doi:10.1146/annurev-physiol-012110-142317. PMID 22335796.
- Ishida, Y.; Nayak, S.; Mindell, J. A.; Grabe, M. (2013). "A model of lysosomal pH regulation". The Journal of General Physiology 141 (6): 705–720. doi:10.1085/jgp.201210930. PMC 3664703. PMID 23712550.
- Alberts, Bruce et al. (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1.
- Lodish, Harvey et al. (2000). Molecular cell biology (4th ed.). New York: Scientific American Books. ISBN 0-7167-3136-3.
- Schultz, Mark L.; Tecedor, Luis; Chang, Michael; Davidson, Beverly L. (2011). "Clarifying lysosomal storage diseases". Trends in Neurosciences 34 (8): 401–410. doi:10.1016/j.tins.2011.05.006. PMC 3153126. PMID 21723623.
- Lieberman, Andrew P.; Puertollano, Rosa; Raben, Nina; Slaugenhaupt, Susan; Walkley, Steven U.; Ballabio, Andrea (2012). "Autophagy in lysosomal storage disorders". Autophagy 8 (5): 719–730. doi:10.4161/auto.19469. PMC 3378416. PMID 22647656.
- Parenti, Giancarlo (2012). "New strategies for the treatment of lysosomal storage diseases (Review)". International Journal of Molecular Medicine 31 (1): 11–20. doi:10.3892/ijmm.2012.1187. PMID 23165354.
- Rosenbloom, Barry E.; Weinreb, Neal J. (2013). "Gaucher Disease: A Comprehensive Review". Critical Reviews in Oncogenesis 18 (3): 163–175. doi:10.1615/CritRevOncog.2013006060. PMID 23510062.
- Sidransky, E (2012). "Gaucher disease: insights from a rare Mendelian disorder.". Discovery Medicine 14 (77): 273–81. PMID 23114583.
- De Duve, C; De Barsy, T; Poole, B; Trouet, A; Tulkens, P; Van Hoof, F (1974). "Commentary. Lysosomotropic agents". Biochemical pharmacology 23 (18): 2495–531. doi:10.1016/0006-2952(74)90174-9. PMID 4606365.
- Trapp, S; Rosania, GR; Horobin, RW; Kornhuber, J (2008). "Quantitative modeling of selective lysosomal targeting for drug design". European Biophysics Journal : EBJ 37 (8): 1317–28. doi:10.1007/s00249-008-0338-4. PMC 2711917. PMID 18504571.
- Kornhuber, J; Schultz, A; Wiltfang, J; Meineke, I; Gleiter, CH; Zöchling, R; Boissl, KW; Leblhuber, F; Riederer, P (1999). "Persistence of haloperidol in human brain tissue". The American Journal of Psychiatry 156 (6): 885–90. PMID 10360127.
- Kornhuber, J; Weigmann, H; Röhrich, J; Wiltfang, J; Bleich, S; Meineke, I; Zöchling, R; Härtter, S; Riederer, P; Hiemke, C (2006). "Region specific distribution of levomepromazine in the human brain". Journal of Neural Transmission (Vienna, Austria : 1996) 113 (3): 387–97. doi:10.1007/s00702-005-0331-3. PMID 15997416.
- Kornhuber, J; Quack, G; Danysz, W; Jellinger, K; Danielczyk, W; Gsell, W; Riederer, P (1995). "Therapeutic brain concentration of the NMDA receptor antagonist amantadine". Neuropharmacology 34 (7): 713–21. doi:10.1016/0028-3908(95)00056-c. PMID 8532138.
- Kornhuber, J; Tripal, P; Reichel, M; Terfloth, L; Bleich, S; Wiltfang, J; Gulbins, E (2008). "Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model". Journal of Medicinal Chemistry 51 (2): 219–37. doi:10.1021/jm070524a. PMID 18027916.
- 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 (2011). Riezman, Howard, ed. "Identification of novel functional inhibitors of acid sphingomyelinase". PloS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365.
- Kornhuber, J; Tripal, P; Reichel, M; Mühle, C; Rhein, C; Muehlbacher, M; Groemer, TW; Gulbins, E (2010). "Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A novel pharmacological group of drugs with broad clinical applications". Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 26 (1): 9–20. doi:10.1159/000315101. PMID 20502000.
- Marty, Francis (1999). "Plant Vacuoles". Tha Plant Cell 11 (4): 587–599. doi:10.2307/3870886.
- Šamaj, Jozef; Read, Nick D.; Volkmann, Dieter; Menzel, Diedrik; Baluska, František (2005). "The endocytic network in plants". Trends in Cell Biology 15 (8): 425–33. doi:10.1016/j.tcb.2005.06.006. PMID 16006126.
- Matile, P (1978). "Biochemistry and Function of Vacuoles". Annual Review of Plant Physiology 29 (1): 193–213. doi:10.1146/annurev.pp.29.060178.001205.
- Moriyasu, Y.; Ohsumi, Y. (1996). "Autophagy in Tobacco Suspension-Cultured Cells in Response to Sucrose Starvation". Plant Physiology 111 (4): 1233–1241. PMC 161001. PMID 12226358.
- Jiao, B.-B.; Wang, J.-J.; Zhu, X.-D.; Zeng, L.-J.; Li, Q.; He, Z.-H. (2011). "A Novel Protein RLS1 with NB-ARM Domains Is Involved in Chloroplast Degradation during Leaf Senescence in Rice". Molecular Plant 5 (1): 205–217. doi:10.1093/mp/ssr081. PMID 21980143.
- Sarah J. Swansona, Paul C. Bethkea, and Russell L. Jonesa (1998). "Barley Aleurone Cells Contain Two Types of Vacuoles: Characterization of Lytic Organelles by Use of Fluorescent Probes". The Plant Cell 10 (5): 685–689. doi:10.2307/3870657.
- Holtzman, Eric (1989). Lysosomes. New York: Plenum Press. pp. 7, 15. ISBN 978-0306-4-3126-5.
- De, Deepesh N. (2000). Plant Cell Vacuoles: An Introduction. Australia: Csiro Publishing. ISBN 9780643099449.
|Look up lysosome in Wiktionary, the free dictionary.|
- 3D structures of proteins associated with lysosome membrane
- Hide and Seek Foundation For Lysosomal Research Team
- Self-Destructive Behavior in Cells May Hold Key to a Longer Life
- Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
- Animation showing how lysosomes are made, and their function