Lysosome structure and function

Lysosome is membrane enclosed cellular organelle that possess distinct enzymes capable of digesting the unwanted or damaged cellular polymers, proteins, DNA and RNA, carbohydrates, and lipids. Lysosome also involved in the breakdown of pathogenic particles especially organic toxins and viral proteins in order to reduce the cause of disease.  The other function of lysosomes is digesting the fragments of unwanted or aged cellular organelle such as mitochondrion.

 

Key points:
  1. Lysosomes popular as suicidal bags of the cell and also referred as recycle bin of the cell.
  2. The lysosomes are single membrane acidic compartments, that contain a bunch of acid hydrolases.
  3. Lysosome present in only animal cells but absent in plant cell, where lysosome function is undertaken by vacuoles or sperosomes.
  4. In side of the lysosome contains high acidic pH compared to cytoplasm of the cell. This acidic nature of the lysosomes due to presence of V-class proton pumps on lysosomal membrane. That pumps the protons from cytoplasm to inside of the lysosomes, which require energy.
  5. They have several important roles in cellular metabolism such as the degradation of extracellular proteins engulfed by endocytosis as well as the turnover of cytoplasmic organelles and cytosolic proteins.
  6. Lysosome contains more than 50 types of hydrolytic enzymes.
  7. Lysosomal enzymes however inactive at physiological pH (7.0 to 7.8), they can only catalyze the enzymatic reaction at their optimal acidic pH.
  8. If lysosomal membrane breaks down, then the enzymes become inactive at cytosolic pH.
  9. Acid phosphatase is marker enzyme of lysosomes because lysosomes can be recognized by staining the acid phosphatase enzyme.
  10. In some cases, Cathepsin is also considered as marker enzyme of lysosomes.
  11. Lysosomes contain the enzyme labilase that makes the lysosomal membrane labile.
  12. The lysosomes also contain the molecule, stabilises, that stabilizes the lysosomal membraneg. cholesterol.
  13. Intracellular compartments, such as aged organelles, are taken into a lysosome by a process called autophagy. For instant, when a mitochondrion comes to the end of its ten-day life, it is engulfed by membrane derived from the endoplasmic reticulum. This ER membrane enclosed mitochondrion vesicle then fuses with a lysosome, resulting in digestion of old mitochondria.
  14. Several defects in the gene that encodes particular lysosomal enzyme have been discovered. The specific defect in the functional gene may result in reduced enzymic production, affected enzymic activity within the lysosomal environment, inappropriate localization of the enzyme within the lysosome, or faulty post-translational modification of the enzyme.

 

1. Lysosome Structure

Lysosomes are formed by budding off of the Golgi apparatus, and the hydrolytic enzymes within them are formed in the endoplasmic reticulum. The enzymes are tagged with the molecule mannose-6-phosphate, transported to the Golgi apparatus in vesicles, and then packaged into the lysosomes.

Structurally lysosomes are very tiny organelle, ranging from 0.1 to 1.2 µm.  They have simple structure covered by membrane, which is made up of phospholipid bilayer. Inside the lysosome various acid hydrolase enzymes are present.

The lipids, especially phospholipids present in the membrane system contain hydrophilic phosphate group heads, a glycerol molecule, and hydrophobic fatty acid tails.

Due to this amphipathic nature, phospholipids typically form membrane bilayers when kept in a solution-containing water. In which, phosphate group heads (hydrophilic) turn towards outside of the layer and interact with water (hydrophilic environment), while the hydrophobic fatty acid tails turn towards inside of the layer (hydrophobic environment) to keep away from water. In this way, phospholipids form many other membranes including cell membrane and membrane of cellular organelles such as nucleus, mitochondria, chloroplast, lysosome, Golgi apparatus, and the endoplasmic reticulum.

 

2. Lysosomal enzymes

Base on their catalytic activity on particular type of bond, enzymes (acid hydrolases) of lysosomes have been divided in to three group.

  1. Acid hydrolases, that act on glycosidic bond.
  2. Glucosidase: This enzyme involved in digestion of complex carbohydrates such as glycogen and starch into their monomers. Glucosidase catalyzes the removal of individual glucosyl residues (monomers) from various glycoconjugates including alpha- or beta-linked polymers of glucose. This enzyme converts complex sugars into simpler one.
  3. Mannosidase: This enzyme plays crucial role in lysosomes that cleaves the cleavage of complex sugar molecules especially mannose-containing oligosaccharides attached to certain proteins (glycoproteins).
  4. Beta galactosidase: This enzyme also called as lactase that catalyzes the hydrolysis of β-galactosides into their monomers through the breaking of a glycosidic bond. β-galactosides are carbohydrates, they contain galactose molecule in their structure, in which the glycosidic bond lies above the galactose molecule.
  5. Lysozyme: Lysozyme, also called as muramidase or N-acetylmuramide glycanhydrolase is an antibacterial enzyme that catalyzes the cleavage of bacterial cell wall, which contains N-acetylglucosamine and N-acetylmuramicacid.
  6. Acid hydrolases, that act on ester bond.
  7. Phospholipase: A phospholipase is crucial enzyme in lysosomes that catalyzes the hydrolyzes phospholipids into fatty acids and glycerol or other fatty substances. There are four main types of this enzymes such as A, B, C and D, which are classified based on the type of enzymatic reaction which they carryout.
  8. Sphingomyelinase: This enzyme also known as Sphingomyelin phosphodiesterase, Acid sphingomyelinase, or SMase) is a hydrolase enzyme that is very important in sphingolipid metabolism. Sphingomyelinase is belonging to the DNase I superfamily of enzymes and catalyzes the hydrolysis of sphingomyelin (SM) into phosphocholine and ceramide.
  9. Acid phosphatase: Acid phosphatase also know as acid phosphomonoesterase, Acid monophosphatase, Acid phosphohydrolase, Acid phosphomonoester hydrolase, Acid nucleoside diphosphate phosphatase, Phosphomonoesterase, Glycerophosphatase, Uteroferrin, or Orthophosphoric-monoester phosphohydrolase. This enzyme catalyzes the hydrolases of organic phosphates into inorganic phosphate. They can use multiple of substrates, which are bound by phosphate group. Acid phosphatase located in lysosomes and performs its functions when it fuses with endosomes, which is acidified during its function; therefore, it should require acid pH. This enzyme is found in many animal and plant species. During typical and pathological bone resorption, osteoclastic acid phosphatase is produced in bulk amount by active osteoclasts. In the past, they were also used as diagnostic marker to distinguish the which type of cancer.
  10. Acid hydrolases, that act on peptide bonds.
  11. Cathepsin: Cathepsins are proteolytic enzymes found in lysosomes of all animals as well as other organisms. Based on the structural difference, rate of catalytic mechanism, or specificity towards particular catalytic site (amino acid in protein) or substrate protein, these enzymes have been divided in to around twelve families. Most of these enzymes show potential activity at low pH found in lysosomes. Thus, the activity of this family found almost within those organelles. However, one exception is there are one type of enzyme such as cathepsin K, which catalyzes the proteins extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have taken major role in mammalian cellular turnover.
  12. Carboxypeptidase: Carboxypeptidase is also a proteolytic enzyme that acts on peptide bond and cleaves it at the carboxy-terminal (C-terminal) end of a protein or peptide. Carboxypeptidases are present in both animals, and plants. Various types of this enzymes are found in these living things and that show diverse functions ranging from catabolism to protein modification.

 

3. Lysosomal polymorphism

Lysosomes are polymorphic, which means functionally they appear in different forms.

  1. Primary lysosomes
  2. Phagolysosomes
  3. Autophagosomes
  4. Residual bodies

Primary lysosomes: This type of lysosomes is formed by fusion of golgi vesicles with late endosomes.

Phagolysosomes: These types of lysosomes are also called digestive vacuoles or heterophagosomes (Phagosome + lysosome = phagolysosome).

Autophagosomes: This type of phagosomes will be formed during the cellular degradative mechanisms called autophagy. It involves renovation and turnover of cellular components degenerate and own and turn parts are removed by autophagy example Mitochondria, ER, peroxysomes, GC (matriphagy). Autophagy also occurs during starvation in liver to provide nutrition for the remaining constuvents.

Residual bodies: These also known as telolysosomes, that contain undigested materials.

 

4. Lysosome function in animal cell
  1. The lysosome function in the animal cell plays a pivotal role in maintaining the cellular homeostasis.
  2. Lysosome involved in intracellular digestion as well as digestion of extracellular components.
  3. Ex: The bone resorptive cell, Osteoclast involved extracellular digestion by releasing the enzymes of lysosomes outside of the cell.
  4. Play a major role in autophagy
  5. Lysosomes involved in crinophagy (secretion), in which removal of excess secretory granules takes place.
  6. Lysosome participates in dissolution of blood clots.
  7. Acrosome is a modified lysosome that present at the tip of the sperm and involved in the fertilization
  8. Lysosome also involved in phagocytosis.
  9. Lysosome also play crucial role during starvation in order to provide nutrients to the body.
  10. Involved in secretion of thyroid
  11. Involved in development of organism, e.g. degradation of tadpole tail during metamorphous by lysosomal enzymes called
  12. Involved in regression of structures or organs after a period of activity, e.g. Uterus, Mullerian, Wolffian bags.
  13. Lysosome is very important organelle in antigen presenting cells and proteolytic cells, e.g. macrophages (scavenging cells of the immune system) to digest the pathogenic molecule. Hence, the abnormal macrophages in the immune system are considered as diagnostic marker for Gaucher’s disease.

 

5. Lysosome-mediated protein degradation

Delivery of foreign or cellular protein to lysosomes. Lysosomes are terminal compartments of the endocytic and autophagic pathways. Newly synthesized lysosomal proteins are delivered to them from the trans-Golgi network via early endosomes, recycling endosomes, and late endosomes/multivesicular bodies. Following lysosome fusion with late endosomes to form an endolysosome, lysosomes are re-formed by a maturation process.

 

6. Clinical correlation

Defective lysosomes have been implicated in Rheumatoid arthritis, Gout, accumulation of uric acid crystals, Silicosis, Asbestosis, Black lung disease, Byssinosis (cotton dust), Acidosis, Anoxia, Chronic granulomatous disease.

 

7. Possible symptoms of Lysosomal storage disease

Affected individuals will experience intellectual disability, skeletal abnormalities, and distinctive facial features. These abnormal characteristic facial features include a large head, prominent forehead, low hairline, rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, overgrown gums, and large tongue.

Abnormalities in skeletal system include bones thickening at the top of the skull (calvaria), bones deformations in the spine (vertebrae), reduced bone density (osteopenia), bowed legs or knock knees, and deterioration of the bones and joints.

Most of the lysosomal storage diseases result from defective or deficiencies of single functional lysosomal enzyme.  Mutations in the genes that encode the proteins or enzymes of lysosome are responsible for more than 40 different human genetic diseases, which are called lysosomal storage diseases because unwanted or unfolded material accumulates within the lysosomes of affected individuals.

For instant, the gene, MAN2B1 is accountable for development of this lysosomal storage disease. In normal conditions, this gene provide the information to synthesize the functional enzyme called alpha-mannosidase, which found in the lysosome. This functional enzyme plays a pivotal role in cleavage of complex sugar molecules (oligosaccharides) into monomers, that are attached to certain proteins (glycoproteins). In particular, alpha-mannosidase helps break down of oligosaccharides containing a monomeric sugar molecule called mannose. Mutation of the gene, MAN2B1, result in synthesis of defective enzyme or complete deficiency of the enzyme occurs. Absence of the enzyme linked to accumulation of mannose molecules in the lysosomes, which damages the body cells. Progressive damage of body cells of the person results in loss of life.

Other example: Pompe disease (one of the most common of lysosomal disease) developed due to irreversible mutations in the gene that encodes a lysosomal enzyme, acid alpha-glucosidase, which is required for the breakdown of glycogen. An interesting exception is I-cell disease, which is caused by a deficiency in the enzyme that catalyzes the first step in the tagging of lysosomal enzymes with mannose-6-phosphate in the Golgi apparatus. The result is a general failure of lysosomal enzymes to be incorporated into lysosomes.

 

References

  1. The Cell: A Molecular Approach. 2nd edition.
  2. Andrea Ballabio. The awesome lysosome. EMBO Mol Med. 2016 Feb; 8(2): 73–76.
  3. Paul Saftig. Chapter 3Physiology of the lysosome. Oxford: Oxford Pharma Genesis; 2006
  4. Haoxing Xu and Dejian Ren. Lysosomal Physiology. Annu Rev Physiol. 2015; 77: 57–80.
  5. Lysosomal membrane dynamics: structure and interorganellar movement of a major lysosomal membrane glycoprotein. J Cell Biol. 1986 May 1; 102(5): 1593–1605.
  6. Alberts B, Johnson A, Lewis J, et al. Transport from the Trans Golgi Network to Lysosomes. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
  7. Frances M. Platt, Barry Boland, Aarnoud C. van der Spoel. Lysosomal storage disorders: The cellular impact of lysosomal dysfunction. J Cell Biol. 2012 Nov 26; 199(5): 723–734.
  8. Debjyoti Bandyopadhyay, Austin Cyphersmith, Jairo A. Zapata, Y. Joseph Kim, and Christine K. Payne. Lysosome Transport as a Function of Lysosome Diameter. PLoS One. 2014; 9(1): e86847.
  9. Paul Luzio, Yvonne Hackmann, Nele M.G. Dieckmann, and Gillian M. Griffiths. The Biogenesis of Lysosomes and Lysosome-Related Organelles. Cold Spring Harb Perspect Biol. 2014 Sep; 6(9): a016840.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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