A lysosome () is a membrane-bound organelle that is found in all animal cells (except red blood cells), and rarely in plant cells. There are normally hundreds of lysosomes in the cytosol, where they function as the cell's degradation center. Their primary responsibility is for catabolic degradation of proteins, polysaccharides and lipids into their respective building-block molecules: amino acids, monosaccharides, and free fatty acids. The breakdown is done by various enzymes, for example proteases, glycosidases and lipases.
With an acidic lumen limited by a single-bilayer lipid membrane, the lysosome holds an environment isolated from the rest of the cell. The lower pH creates optimal conditions for the over 60 different hydrolases inside.
Lysosomes receive extracellular particles through endocytosis, and intracellular components through autophagy.
Function and structure
thumb|TEM views of various vesicular compartments. Lysosomes are denoted by "Ly". They are dyed dark due to their acidity; in the center of the top image, a [[Golgi Apparatus can be seen, distal from the cell membrane relative to the lysosome.]]
Lysosomes vary in shape and size depending on their state, what they are digesting, and the cell type they are in. Their shape can differ from spherical and ovoid to occasionally tubular. The size of lysosomes ranges from 0.1-1.2 μm,
The lysosomal membrane is a phospholipid bilayer with high carbohydrate content from heavily glycosylated membrane proteins. This forms a glycocalyx that protects the cell from the degradative enzymes held within the lysosome. Lysosomal hydrolases are pH-sensitive and do not function properly in the alkaline environment of the cytosol, ensuring that molecules and organelles in the cytosol are not degraded if there is leakage of hydrolytic enzymes from the lysosome.
In addition to breaking down polymers, lysosomes are capable of killing and digesting microbes, cells, or cellular debris. Through cooperation with phagosomes, lysosomes conduct autophagy, clearing out damaged structures and forming simple compounds, which are then used as new building materials. Similarly, lysosomes break down virus particles or bacteria during phagocytosis in macrophages.
Lysosomes also help detect pathogens through toll-like receptors (TLRs), like TLR7 and TLR9. Microbes can be degraded into antigens, which are then loaded onto MHC molecules and presented to T-cells, a critical part of immune defense. Additionally, lysosomal enzymes can trigger lysosomal-mediated programmed cell death (LM-PCD) if released into the cytoplasm.
To maintain their acidic environment, lysosomes pump protons (H⁺ ions) from mitochondria into the lysosomal lumen via a proton pump in the lysosomal membrane. Vacuolar-ATPases are responsible for the transport of protons, while the counter transport of chloride ions is performed by ClC-7 Cl⁻/H⁺ antiporter. This mechanism helps maintain a steady acidic environment, as well as ionic homeostasis, within the lysosome.
Lysosomes also help balance cellular metabolism by sensing nutrient availability. When nutrients are plentiful, they activate mTOR signaling to support anabolic (biosynthetic) processes. During starvation, lysosomes degrade autophagic material, recycling components to maintain cell survival.
Lysosomal degradation pathways
thumb|399x399px|Cellular material is delivered to lysosomes in four different ways; (A) Macroautophagy, (B) Endosomal degradation, (C) Microautophagy and (D) Chaperone-mediated autophagy (CMA).
The lysosome is delivered material for degradation via transient interactions or complete fusion, forming endolysosomes and autolysosomes respectively. This way, the lysosomes act as reservoirs for acidic hydrolases, cycling through fusion and fission events with late endosomes and autophagosomes. The actual breakdown of endocytic and autophagic cargo primarily happens within these transient structures—endolysosomes and autolysosomes—under normal physiological conditions. allowing them to be sorted into vesicles. These vesicles then bud off from the trans-Golgi network and fuse with early endosomes.
Early endosomes degrade cargo from the extracellular environment, and as they mature into late endosomes, proton pumps are activated, causing the internal environment to become acidic. This acidic environment activates the hydrolytic enzymes, which further mature the endosome into a lysosome. The lysosome then breaks down and recycles cellular waste.
Disruptions in lysosomal formation can lead to dysfunctional lysosomes and the accumulation of undigested molecules, contributing to various lysosomal storage disorders.
Just like other pathogens, viruses entering the cell via endocytosis are degraded in lysosomes. However, some viruses have evolved strategies to escape degradation by lysosomes, and are able to escape the lysosome before complete degradation and spread viral material into the cytoplasm which then spreads viral infection in the cell. Poor lysosomal activity and failure by lysosomes to properly degrade all biomolecules from pathogens results in higher viral infections by viruses such as HIV.
Clinical significance
Lysosomal storage disorders are a group of metabolic disorders that stem from inherited genetic mutations that disrupt normal lysosomal function and homeostasis. Most frequently, the mutations are located in the acidic hydrolases, but can also be found in non-enzymatic lysosomal proteins (soluble and membrane-bound) and non-lysosomal factors controlling lysosomal function. This leads to defective degradation, which induces abnormal accumulations of undigested or partially digested macromolecules within lysosomes. Lysosomal dysfunction also affects transport across the lysosomal membrane, vesicle trafficking, lysosome reformation and autophagy.
The age of onset and the specific symptoms in lysosomal storage disorders differ depending on the severity of the mutations, the cell types affected and what substrates accumulate. However, the clinical presentation is typically a neurodegenerative disease at childhood, with more variations presenting themselves in adulthood. In most cases, the central nervous system (CNS) is affected, causing the brain to experience global neurodegeneration, inflammation, activation of the innate immune system and astrogliosis. This "acid trapping" or "proton pump" effect can be predicted using mathematical models.
Many approved drugs, including haloperidol, levomepromazine, and amantadine, exhibit lysosomotropic behavior. This helps explain their high tissue-to-blood concentration ratios and prolonged tissue retention, though fat solubility also contributes.
Some lysosomotropic drugs can interfere with lysosomal enzymes like acid sphingomyelinase. Ambroxol, a mucolytic, promotes lysosomal exocytosis by neutralizing lysosomal pH and releasing stored calcium. This action may underlie its observed benefits in diseases linked to lysosomal dysfunction, including Parkinson's disease and lysosomal storage disorders.
Systemic lupus erythematosus (Lupus)
Systemic lupus erythematosus (SLE), otherwise known as lupus, is an autoimmune disease where the immune system attacks healthy cells. Lupus 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 rises from irregularly extended activity of mTORC2, which impairs lysosome acidification. As a result, immune complexes in the lysosome recycle to the surface of macrophages causing an accumulation of DNA fragments and nuclear complexes which triggers an immune response from the body which is leads to the multiple lupus-associated pathologies.
Different types of enzymes present in lysosomes
There are over 50 different types of hydrolytic enzymes in lysosomes, the table below shows a few of the main types and their substrates. It is important to keep in mind that each category below has multiple different types of enzymes.
{| class="wikitable"
|+
!Sr. No
!Enzymes
!Substrate
|-
|1
|Proteases
|Proteins and Peptides (breaks peptide bonds)
|-
|2
|Nucleases
|DNA and RNA (cleaves phosphodiester bonds)
|-
|3
|Glycosidases
|Carbohydrates (breaks glycosidic bonds)
|-
|4
|Lipases
|Lipids (breaks ester bonds)
|-
|5
|Phospholipases
|Phospholipids (cleaves fatty acids from phospholipids)
|-
|7
|Phosphatases
|Phosphorylated molecules (removes phosphate groups)
|-
|8
|Sulfatases
|Sulfated molecules (removes sulphate groups)
|}
See also
- Peroxisome
- Cathelicidin
- Antimicrobial peptides
- Innate immune system
- TMEM106B
- Endosomes