A vacuolar structure that contains hydrolytic enzymes which function at an acidic pH and is surrounded by a membrane that protects the cell from their action.
A lysosome is a membrane-bound organelle found in many cells.
Lysosomes are primarily responsible for the enzymatic degradation of the components of the cell in a process called autophagy.
They are spherical vesicles that contain hydrolytic enzymes that can break down biomolecules.
The size of lysosomes varies from 0.1 μm to 1.2 μm.
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).
A cytoplasmic organelle that contains hydrolytic enzymes.
Lysosomes participate in many cellular functions: immunity, gene regulation, nutrient sensing, and plasma membrane repair, homeostasis, and apoptosis, secretion, cell signaling, energy metabolism, aging, along with it enzymatic degradation degradation.
The enzymes responsible for this hydrolysis require an acidic environment for optimal activity.
Lysosomes 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.
Material from the inside of the cell is digested through autophagy.
The sizes of the organelles vary greatly.
Lysosomes are known to contain more than 60 different enzymes, and have more than 50 membrane proteins.
Lysosomes digest materials taken into the cell and recycle intracellular materials.
Lysosomes contain a variety of enzymes, enabling the cell to break down various biomolecules it engulfs, including peptides, nucleic acids, carbohydrates, and lipids.
Lysosomal enzymes are synthesized in the rough endoplasmic reticulum and exported to the Golgi apparatus.
The enzymes are moved 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.
Most lysosomal enzymes and membrane proteins are controlled by transcription factor EB (TFEB), which promotes the transcription of nuclear genes.
Mutations in the genes for these enzymes are responsible for more than 50 different human genetic disorders, the lysosomal storage diseases.
These diseases result from an accumulation of specific substrates, due to the inability to break them down.
These genetic defects are related to several neurodegenerative disorders, cancers, cardiovascular diseases, and aging-related diseases.
The large majority of these lysosomal diseases are caused by damaging mutations in genes that encode lysosomal enzymes.
Each enzyme is responsible for the degradation of a substrate that enters the lysosome by means of autophagia.
Deficiency of lysosomal enzyme leads to an accumulation of its substrates but also to the disturbance of other cellular processes for which the lysosome is a regulator.
Lysosomal disorders differ because lysosomal enzymes are tissue specific.
Lysosomes are able to break down polymers, and are capable of fusing with other organelles to digest large structures or cellular debris.
Working with phagosomes, they are able to conduct autophagy, clearing out damaged structures.
Lysosomes are able to break down virus particles or bacteria in phagocytosis of macrophages.
The lysosomal membrane protects the cytosol, and the rest of the cell, from the degradative enzymes within the lysosome.
Lysosomal acid hydrolases that drain into the cytosol are pH-sensitive and do not function well or at all in the alkaline environment of the cytosol, protecting the cell’s cytosolic molecules and organelles from destroyed in case there is leakage of the hydrolytic enzymes from the lysosome.
It is thought that lysosomes participate in the 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 that is controlled by transcription factor EB (TFEB).
mRNA transcripts exit the nucleus into the cytosol, where they are translated by ribosomes, and they are translocated into the rough endoplasmic reticulum, where they are modified.
Lysosomal soluble proteins exit the endoplasmic reticulum via coated vesicles .
Vesicles then deliver lysosomal enzymes to the Golgi apparatus, where a specific lysosomal tag, mannose 6-phosphate, is added to the peptides.
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 lysosome also acts as a safeguard in preventing pathogens from being able to reach the cytoplasm before being degraded.
Lysosomes prevent easy entry into the cell by hydrolyzing the biomolecules of pathogens necessary for their replication.
Reduced Lysosomal activity results in an increase in viral infectivity, including HIV.
The AB5 toxins such as cholera hijack the endosomal pathway while evading lysosomal degradation.
Lysosomes are involved in 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 likely higher as many cases are likely to be undiagnosed or misdiagnosed.
The primary cause is deficiency of an acid hydrolase, while other conditions are due to defects in lysosomal membrane proteins that fail to transport the enzyme, non-enzymatic soluble lysosomal proteins.
The effect of such disorders is the accumulation of macromolecules or monomeric compounds inside the endosomal–autophagic–lysosomal system, resulting in abnormal signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking, ultimately leading to pathogenetic disorders.
The organs most affected by lysosomal storage diseases are the brain, viscera, bone and cartilage.
Lysosomal disorders manifest as a spectrum of phenotypes, the
severity of which and the disease progression that is determined by the specific type of disease, causing mutation and level of residual enzyme activity.
If a mutation occurs that ablates protein production, the disease is severe, with fetal demise of death in infancy or early childhood.
If the mutation is mild disease, manifestation may be mild to moderate.
Most recombinant proteins that are used to treat lysosomal disorders carry a sugar resident, mannose-6-phosphate (M6P), which binds to the M6P receptor on the surface of cells.
The M6P receptor is critically important for a healthy people or for enzyme replacement therapy in people with lysosomal storage disorders.
Each cell produces its own lysosomal enzymes.
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.
In Gaucher’s disease 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.
Enzyme replacement therapy is available for treating many known LDs.
The most severe and rarely found, lysosomal storage disease is inclusion cell disease.
Metachromatic leukodystrophy is a lysosomal storage disease that also affects sphingolipid metabolism.
Dysfunctional lysosome activity is also heavily implicated in the biology of aging, and age-related diseases such as Alzheimer’s, Parkinson’s, and cardiovascular disease.
Different enzymes present in Lysosomes
Phosphates
Acid phosphatase
Acid phosphodiesterase
Nucleases
Acid ribonuclease RNA
Acid deoxyribonuclease DNA
Polysaccharides/ mucopolysaccharides hydrolyzing enzymes
β-Galactosidase Galactosides
α-Glucosidase Glycogen
α-Mannosidase Mannosides, glycoproteins
β- Glucoronidase Polysaccharides and mucopolysaccharides
Arylsulphatase
Proteases
Cathepsin(s)
Collagenase
Peptidase Peptides
Lipid degrading enzymes
Esterase Fatty acyl esters
Phospholipase Phospholipids
Sulfatases
Weak bases with lipophilic properties accumulate in acidic intracellular compartments like lysosomes: lysosomotropism
A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties.
Some disease of lysosomal origin include Parkinson’s disease.
Impaired lysosome function is prominent in systemic lupus erythematosus preventing macrophages and monocytes from degrading neutrophil extracellular traps and immune complexes.
The failure to degrade internalized immune complexes stems from chronic mTORC2 activity, which impairs lysosome acidification.
Immune complexes in the lysosome recycle to the surface of macrophages causing an accumulation of nuclear antigens upstream of multiple lupus-associated pathologies.
The lysosome maintains its pH protective differential by pumping in protons (H+ ions) from the cytosol across the membrane via proton pumps and chloride ion channels.
A steady acidic environment is maintained by
vacuolar-ATPases are responsible for transport of protons, while the counter transport of chloride ions is performed by ClC-7 Cl−/H+ antiporter.
It has a variable capacity for degradation of import by enzymes with specificity for different substrates: cathepsins are the major class of hydrolytic enzymes, while lysosomal alpha-glucosidase is responsible for carbohydrates, and lysosomal acid phosphatase is necessary to release phosphate groups of phospholipids.
In Gaucher’s disease the accumulation of sphingolipids occurs primarily in macrophages and Kupffer cells causing hepatosplenomegaly.
In mucopolysaccharidoses the accumulation of glycosaminoglycans in connective tissue and cartilage, explains the coarse facial features and short stature observed in patients.
In Pompe’s disease, deficiency of acid alpha-glucosidase3 results in the accumulation of glycogen which primarily affects muscle.
Three types have been identified: primary, secondary, and tertiary.
Responsible for intracellular digestion of phagocytocized or damaged, worn out or other disposed cellular components.
May fuse with vacuoles containing foreign substances engulfed by the cell.
Rupture of lysosomes can release enzymes and autolye cells.
Digestive processes are dynamic and involves digestion of exogenous proteins, exogenous particles and digestion of endogenous proteins and cell organelles.
The digestion of exogenous proteins occurs by targeting through receptor mediated endocytosis and pinocytosis while exogenous particles are targeted by phagocytosis and the two activities are referred to as heterophagy.
The lysosome/vacuolar system is a heterogeneous digestive system that includes structures without hydrolases and residual bodies which are the end products of digestion of proteins both heterophagy and autophagy.
Indicates that cellular proteins are in a constant state of synthesis and degradation
Autophagy is the basic mechanism of function whereby portions of the cytoplasm which contain all of the cellular proteins are segregated within a membrane compartment and fuse to a primary lysosome and their contents digested.
With extreme situations such as starvation mitochondria, endoplasmic reticulum membranes, glycogen and other cytoplasmic elements can be engulfed by macroautophagy.
Extracellular materials ingested via endocytosis of phagocytes, are enveloped by a temporary vesicle (endosome) that fuses with the lysosome with enzymatic degradation of the endosomal contents.
The nucleases, proteases and phosphatases lysosomal enzymes are activated at a pH of 4.8.
pH of lysosome maintained by a lysosomal membrane hydrogen pump that hydrolyzes ATP to move protons against the concentration gradient.