Graduate Cell Biology · The Acid Organelle
The Lysosome
Christian de Duve’s 1955 “suicide bag” — the cell’s acidic catabolic compartment, its autophagy terminus, and, more recently, its unexpected metabolic nerve centre.
About This Course
Christian de Duve discovered the lysosome in 1955 through cell fractionation: a dense membrane-bound fraction carrying “latent” acid hydrolases that became active upon Triton-X disruption. He named it the “lysosome” (dissolving body) and shared the 1974 Nobel Prize for the work. For decades the lysosome was regarded primarily as a rubbish-disposal organelle — the cell’s digestive system. The past fifteen years have revolutionised that view.
The lysosome is now understood as a signalling hub: mTORC1 docks on its surface to sense amino acids and nutrient state (Sabatini 2008), TFEBis the master transcriptional regulator of lysosomal biogenesis, and galectin surveillance polices membrane damage. The seven modules cover architecture, acidification, the hydrolase arsenal, delivery pathways, > 50 lysosomal storage disorders, the mTORC1 story, and the lysosome’s emerging central role in neurodegeneration.
Seven Modules
M0
Discovery & Architecture
De Duve 1955 cell fractionation (1974 Nobel), 250-1000 nm organelle, limiting membrane (LAMP1/2, heavily glycosylated), ~60 soluble hydrolases.
M1
V-ATPase & Acidification
Rotary V1V0 V-ATPase structure, 2:1 H+/ATP stoichiometry, ClC-7 chloride counter-ion, pump-leak balance, steady-state pH 4.5-5.0.
M2
Hydrolases & pKa Engineering
Cathepsins A/B/D/K/L, glycosidases, sulfatases, lipases. pKa-tuned active sites; cytosolic release catastrophe; lysosomal fail-safe design.
M3
Delivery Pathways
Endocytosis (clathrin, caveolae), phagocytosis (actin-driven), macropinocytosis, autophagy (macro/micro/CMA) via Ohsumi ATG genes.
M4
Lysosomal Storage Disorders
>50 inborn errors. Gaucher (GBA), Fabry (GLA), Pompe (GAA), Niemann-Pick, Tay-Sachs. ERT, substrate reduction, gene therapy, GBA-PD link.
M5
mTORC1 at the Lysosome
Sabatini: mTORC1 on lysosomal surface, Rag GTPases, Ragulator, amino-acid sensing (CASTOR, SAMTOR, Sestrin), rapamycin mechanism, cancer targeting.
M6
Lysosome in Neurodegeneration
GBA1 heterozygosity and Parkinson’s disease, progranulin/FTD, lysosomal-membrane permeabilization (LMP), galectin-8 lysophagy, TFEB master switch.
Cross-Links
Organelles,Endoplasmic Reticulum,Golgi,Mitochondria,Stem Cells.