Lysosomes 2024-2025 PDF

Lysosomes Asst. Prof. Burcu TÜRKGENÇ Dept. of Medical Biology  Lysosomes are principal sites of intracellular digestion Lysosomes are membrane enclosed organelles Filled with hydrolytic enzymes that control digestion of macromolecules 2 ...

Lysosomes Asst. Prof. Burcu TÜRKGENÇ Dept. of Medical Biology  Lysosomes are principal sites of intracellular digestion Lysosomes are membrane enclosed organelles Filled with hydrolytic enzymes that control digestion of macromolecules 2  Lysosomes are dense rounded bodies About 300 Lysosomes are found in each cell 0. 5 - 1 μm in diameter. Their size and shape varies according to the material that is taken up for digestion. They are abundant in cells specialized for phagocytosis such as macrophages and neutrophilic granulocytes 3  Lysosomes are found in all animal cells except for erythrocytes In plant cells lysosomes are not found but they contain very large vacuoles that are related to lysosomes and contain hydrolytic enzymes 4  Lysosomes Lysosomes contain about 60 different degradative enzymes that can hydrolyze proteins, DNA, RNA, polysaccharides, and lipids. Lysosomal Acid Hydrolases- Proteases Nucleases Glycosidases Lipases Phosphatases Sulphatases they are active at acidic pH (pH 4.5-5) but not in neutral pH (7.2) of the cytoplasm 5  Lysosomal Enzymes Nucleic acid degradation Protein degradation RNases Catepsin DNases Collagenases Carbohydrate degradation Phosphatases ɑ Galactosidases Acid Phosphatases β Galactosidases Acid phosphodiesterases Lysosyme Sulphatases Mucopolysaccharide degradation Aryl Sulphatases ɑ glucuronidase Hyaluronidases 6  Lysosomes are active at acidic pH to maintain acidic pH: H⁺ ions were pumped into the lysosomes by using the energy of (ATP) hydrolysis. Lysosomal membrane has a proton pump; in which H⁺ ATPase transports protons into the lysosome. 7 Lysosomes are active at acidic pH The requirement of these lysosomal hydrolases for acidic pH provides double protection against uncontrolled digestion of the contents of the cytosol; even if the lysosomal membrane were to break down, the released acid hydrolases would be inactive at the neutral pH of the cytosol. 8  Lysosome membrane Lysosome has a unique membrane. Lysosomal membrane proteins are unusually highly glycosylated at their noncytosolic (Luminal, or interior) surface Form a glycocalyx layer. Which helps to protect membranes from acid hydrolases in the lumen. Lysosomal membranes contain Transport proteins that carry the final products of digestion such as amino acids, sugars and nucleotides to the cytosol 9  Lysosomal enzymes are resistant to proteases and peptidases. Glycosylation of lysosomal proteins protect them from degradation. 10  Vesicles that contain lysosomal enzymes are called primary lysosomes. Primary lysosomes fuse with vesicles that contain material to be digested (late endosomes) and form secondary lysosomes. 11 12  How are Lysosomal proteins recognized and selected in the Golgi (TGN) The lysosomal proteins carry a unique marker in the form of mannose-6-phosphate (M6P) M6P markers are added to the N-linked oligosaccharides of lysosomal enzymes in the lumen of cis-Golgi network. 13  Formation of the primary lysosomes The Golgi complex is responsible for the packing of hydrolytic lysosomal enzymes to form a primary lysosome The lysosomal proteins carry a unique marker in the form of mannoz-6-phosphate (M6P) M6P is added to lysosomal proteins in the lumen of the cis-Golgi network 14  Lysosomal hydrolases The M-6-P groups are recognized by M6P -receptor proteins in the trans-Golgi network. These receptors bind to lysosomal hydrolases and help package the hydrolases into specific clathrin coated transport vesicles that fuse with lysosomes. In the lumen of lysosomes Acidic pH causes the lysosomal enzymes to dissociate from the M6P receptors. lysosomal enzymes are released into the lumen M6P Receptors remain in the membrane and return to the trans Golgi and15 reused (receptor recycling).  Lysosomal hydrolases Lysosomal hydrolases are synthesized in ER. Glycosylated in ER and Golgi. Modified in cis Golgi network by the addition of M6P markers M6P receptors recognize M6P markers at trans-Golgi network Receptor plus enzyme complex are packaged into specific transport vesicles (clathrin coated vesicles) Hydrolases exit from trans-Golgi network by clathrin coated vesicles. 16  Variety of digestive functions that lysosomes mediate Breakdown of intra- and extracellular materials Production of nutrients for the cell Destruction of phagocytosed microorganisms (Defence mechanism) 17 There are three pathways that deliver materials to lysosomes 1-Digestion of macromolecules taken up from extracellular fluid by endocytosis. 2-Digestion of material that are taken up by phagocytosis (Defence against invading bacteria) 3-Autophagy; Digestion of cell’s own components ( i.e senescent organelles) 18 19 End products of lysosomal digestion Amino acids (from proteins) Fatty acids, glycerol and cholesterol (from lipids) Monosaccharides such as glucose, fructose, and galactose (from Polysaccharides a type of carbohydrate) Nucleotides (from nucleic acids) Undigested cellular waste products (e.g., lipofuscin) *End products of lysosomal digestion are transported to the cytosol. 20  Only material which can not be digested (resistant or slowly digestible residues) remain in the vesicle are released from cell by exocytosis or form a membrane enclosed residual body. 21 Residual bodies are vesicles containing indigestible materials. Residual bodies accumulates in neurons, heart muscle cells and liver cells of aging individuals and called lipofuscin pigment or aging pigment and cause Brown degeneration. Lipofuscin is a type of residual body. 22  Lipofuscin pigment or aging pigment Age spots on a hand. Source: Alain Gerard, Creative Commons Attribution Share-alike 4.0. 23  Lysosomal diseases Lysosomal enzyme defects Resulted from mutations in lysosomal enzymes and cause accumulation of the undigested substrates of the defective enzyme and disrupt the cellular functions Lysosomal storage diseases more than 30 Lysosomal storage diseases have been described In general autosomal recessive inheritance 24 Lysosomal storage diseases 25  Examples of Lysosomal diseases 1- Gaucher’s disease: Glucocerebrosidase enzyme defect Glucocerebrosides accumulates in CNS and spleen. *Glucocerebrosides are a class of glycosphingolipids, which are molecules composed of a sphingosine backbone, a fatty acid chain, and a sugar. 2- Niemann-pick disease: Sphingomyelinase enzyme defect Sphingomyelin and Cholesterol acumulates in CNS, spleen and liver. *Sphingomyelin is a type of sphingolipid, which is a subclass of lipids that contain a sphingosine backbone. *Cholesterol is a type of lipid molecule (sterol) that contains a complex ring structure. 3- Tay-Sachs disease: Hexosaminidase A enzyme defect Gangliosides GM2 accumulates in CNS. Gangliosides are a class of glycosphingolipids, which are complex lipids that contain both a sphingolipid backbone and carbohydrates (sugars) attached to them. 26 27 28 Videos: Lysosomes https://www.jove.com/science- education/11961/lysosomes?playlist=74b3c7fd 29