Lysosomes

Single membrane, digestive, hydrolytic reactions. 40 hydrolytic enzymes, heterogenous contents

pH 4-5 (acidic)

v-ATPase - protein complex in the membrane which pumps protons into the lysosome lumen to maintain a low pH Ion channels and transporters Transporters for products of hydrolysis reactions e.g. polysaccharides into sugars Cholesterol transporters for when cholesterol is broken down SNARES, tethering factors for organelle fusion Motor adaptors for motility Signalling complexes - Metabolic signalling, immune responses Transcription factors - Gene regulation, immune responses

Melanocyte Mast cell Basophil Platelet Neutrophil T cell Osteoclast Endothelial cell Neuron

High concentration of melanin, which protects us from sunlight by absorbing UV light

• Endosomes acquire specific proteins to produce melanin, with fusion fission processes with other organelles such as golgi

Produced by melanocytes, transported to keratinocyte

Endocytosis - Fluid-phase endocytsosis of molecules and lipoproteins Phagocytosis of particles Less than 0.5 um

Microautophagy - Invagination of the lysosomal membrane (self-eating - inward budding of the lysosomal membrane) Macroautophagy - Cytosol or organelles wrapped in ER membrane, which then fuses with lysosomes for degradation Selective transport of proteins across the lysosomal membrane

LDL (low-density lipoprotein) which in high conc can cause cardiovascular disease. Helps build membranes. When LDL which contain cholesteryl ester bind to the receptor of the membrane, a coated pit is formed which captures the LDL molecules bound to the receptors. They can pinch off through vesicular budding, in the inside of the cell, forming an endosome. As the pH drops, the LDL particles dissociated from the receptors, and the receptors are recycled to be used again in the membrane. The LDL particles are ultimately delivered to endo/lysosomes, and the ester is hydrolysed to cholesterol and fatty acids.

• The particle binds to the cell surface and is then engulfed, through the membrane wrapping itself around the molecule. This forms a phagosome • The lysosomes will fuse with the phagosome, forming a phagolysosome • The lysosomes deliver hydrolytic enzymes which carry vacular ATPase molecules, proton pumps to maintain low acidic pH in lysosome so enzymes can digest the particle.

From flat to round and more spherical

Take up particles larger than themselves, even simultaneously taking up two cells at once

Organelle forms double membrane which wraps around cytosol/organelles, forming an autophagosome. This fuses with a lysosome to form an autophagolysosome. The lysosome delivers the digestive enzymes and proton pumps to lower pH.

In endocytosis, a viral molecule may be taken up in the endosome. The drop in pH causes the activation of viral proteins that mediate the fusion of the viral membrane with the endosomal membrane, leading to the release of viral contents and infection.

The protein while being synthesised enters the lumen of the ER. A large carbohydrate is transferred onto the protein on an Asparagine residue (N) in N-glycosylation.

One of the mannose sugars in the oligosaccharide structure is phosphorylated to form mannose 6-phosphate.

The mannose 6-phosphate residue is recognised by a specific receptor called the mannose 6-phosphate receptor. The receptor with its m6p modified ligand clusters in the membrane, leading to the formation of budding vesicles called the Clathrin-coat. The vesicles then carry the receptor-mannose modified lysosomal hydrolyses towards the late endosomes, where they are transported to lysosomes.

A lysosomal storage disorder would emerge, and the substrate would accumulate as it cannot be digested due to the missing enzyme.

Sandhoff disease - Defects in an enzyme required for the breakdown of gangliosides. Membrane structures accumulate (multilamellar bodies) inside the lysosome,

This is required for the targeting of ALL hydrolytic enzymes in the lysosome. E.g. I cell disease, no M6P tag, cannot be recognised by M6P receptor, secreted out of the cell and then found in the supernatant and blood rather than the lysosomes. The lysosomes cannot digest anything, although autophagy will continue. Substrates will accumulate in the lysosome.

Dense granular inclusions in fibroblasts from a patient with I cell disease

Skeletal abnormalities, developmental delay, enlarged liver and spleen, impaired hearing, death from pneumonia or congestive heart failure within first decade of life, autosomal-recessive disorder.

Subtle mutations can lead to different phenotypes rather than completely destroying