- Lysosomes and Peroxisomes

Learning Outcomes

After this lecture, you should be able to:

1. Describe how lysosomes are formed via the endocytic and secretory pathways.

2. Explain the functions and degradative pathways of lysosomes, including autophagy and phagocytosis.

3. Describe the likely formation of peroxisomes through de novo biogenesis and fission.

4. Explain how the peroxisome contents enable its function in metabolism and redox balance.

Secretory and Endocytic Pathways

• Pathway components:

  • Endoplasmic Reticulum (ER): Site of translation for lysosomal enzymes.

  • Golgi Apparatus: Sorting hub; cis-Golgi adds M6P tags, trans-Golgi sorts into vesicles.

  • Endosomes: Maturation stages (early to late) before fusion with lysosomes.

  • Plasma Membrane (PM): Source of endocytic vesicles.

Exocytosis

Regulated and Constitutive Pathways

• Constitutive Secretion:

  • Continuous process occurring in all eukaryotic cells.

  • Newly synthesized soluble proteins and PM lipids are transported in vesicles for immediate, unregulated fusion with the PM.

• Regulated Secretion:

  • Found in specialized cells (e.g., endocrine or exocrine).

  • Fusion and release occur only in response to specific extracellular stimuli (e.g., hormones, neurotransmitters, or calcium flux).

Formation and Function of Lysosomes

Formation

• Lysosomes are dynamic organelles formed by:

  • Fusion of transport vesicles from the trans Golgi network carrying acid hydrolases.

  • Fusion with late endosomes, which contain materials internalized via endocytosis.

  • Progress from early endosomes (sorting) to late endosomes (acidifying) to mature lysosomes.

Function

• Compartmentalization:

  • Ensures acidic hydrolases do not damage the neutral cytosol ($pH \approx 7.2$).

• Intracellular Digestion: Breakdown of proteins, nucleic acids, carbohydrates, and lipids.

• Autophagy: A process where the cell digests its own obsolete organelles (e.g., mitochondria) by wrapping them in a double membrane (autophagosome) that fuses with a lysosome.

Structure of Lysosomes

• Membrane Composition:

  • Highly glycosylated membrane proteins (LAMPs and LIMPs) form a protective glycocalyx to prevent self-digestion of the membrane.

  • Vacuolar $H^+$ ATPase: An ATP-dependent proton pump that maintains the acidic environment.

• Size and pH conditions:

  • Internal $pH \approx 5.0$, which is the optimal acidity for hydrolase activity.

• Acid Hydrolases:

  • Includes roughly 40 types of enzymes: nucleases, proteases, glycosidases, lipases, phosphatases, sulfatases, and phospholipases.

Targeting Proteins to Lysosomes

1. Signal Recognition: Proteins destined for lysosomes contain a signal patch recognized by enzymes in the Golgi.

2. M6P Tagging: In the cis-Golgi, mannose residues on the N-linked oligosaccharide are phosphorylated to form Mannose-6-Phosphate (M6P).

3. Receptor Binding: In the trans-Golgi network, M6P receptors bind the M6P tags on the enzymes, concentrating them into clathrin-coated vesicles.

4. Dissociation: Vesicles fuse with late endosomes; the drop in pH causes the enzyme to dissociate from the receptor.

Endocytic Pathways

1. Phagocytosis: "Cell eating"; ingestion of large particles like bacteria into phagosomes.

2. Pinocytosis: "Cell drinking"; non-specific uptake of extracellular fluid and solutes.

3. Receptor-mediated endocytosis: Selective uptake of specific ligands (e.g., LDL).

4. Lysosomal Digestion: The final destination for materials from all active pathways.

Receptor-mediated Endocytosis of LDL

• LDL Binding: LDL particles bind to LDL receptors on the cell surface.

• Coated Pits: Clathrin-coated pits invaginate to form vesicles.

• Uncoating & Fusion: Vesicles lose their clathrin coat and fuse with endosomes.

• Recycling: The acidic pH of the endosome causes LDL to release from the receptor; the receptor is recycled to the PM, while the LDL moves to the lysosome for cholesterol release.

Peroxisomes

• Physical Characteristics: Membrane-bound organelles ($0.2 - 1.5 \mu m$) found in almost all eukaryotes. They lack their own genome and must import all proteins.

• Structure: Single lipid bilayer enclosing a dense crystalline protein core (matrix) in some species.

Functions of Peroxisomes

1. $\beta$-oxidation of Fatty Acids:

   • Peroxisomes are the exclusive site for the breakdown of Very Long Chain Fatty Acids (VLCFAs) in animal cells.

Formation of Peroxisomes

• De novo Synthesis: Precursor vesicles bud from the ER.

• Import and Growth: Specific transport proteins called Peroxins (Pex proteins) import proteins from the cytosol. The organelle grows and then undergoes fission to multiply.

Key Differences: Peroxisomes vs Lysosomes

• Peroxisomes are enclosed in a single membrane (lysosomes also have single membrane).

• Peroxisomes must take up proteins from the cytoplasm.

• Peroxisomes differ from lysosomes in their enzymatic content and metabolic functions.