Lysosome

Lysosomes are membrane-bound organelles present in all mammalian cells except mature erythrocytes. They serve as the primary degradative centres of the cell, breaking down macromolecules, damaged organelles, and internalised material. Their activity supports numerous essential biological processes, including nutrient recycling, immune defence, membrane repair, and cellular homeostasis.

Discovery and Historical Importance

The lysosome was identified in the 1950s by the Belgian biochemist Christian de Duve during studies on the intracellular distribution of hydrolytic enzymes. Using cell fractionation and enzyme assays, de Duve demonstrated the existence of a previously unknown organelle rich in acid phosphatase and other hydrolases. Electron microscopy later confirmed the presence of membrane-bounded vesicles containing these enzymes. His discovery formed the foundation of modern cell biology and contributed significantly to the understanding of intracellular digestion, autophagy, and various diseases. For this work, de Duve received the Nobel Prize in Physiology or Medicine in 1974.

Structure and General Characteristics

Lysosomes vary considerably in size and morphology according to cell type, metabolic state, and the material they are processing. Typically, they are spherical or ovoid organelles ranging from 0.1 to 1.2 µm in diameter, although larger tubular forms may occur in phagocytic cells. Most mammalian cells contain several hundred lysosomes, though this number decreases during nutrient deprivation or enhanced autophagy.
The lysosomal lumen is acidic, with a pH between 4.5 and 5.0. This environment is generated and maintained by V-ATPase proton pumps working in conjunction with chloride ion exchangers such as the ClC-7 Cl⁻/H⁺ antiporter. The acidic pH is essential for the functioning of more than sixty hydrolases, including proteases, lipases, nucleases, and glycosidases.
The limiting membrane of the lysosome consists of a phospholipid bilayer enriched with heavily glycosylated proteins. This creates a protective glycocalyx that shields the membrane from internal digestive enzymes. Importantly, lysosomal hydrolases do not function efficiently at the neutral to slightly basic pH of the cytosol, offering an additional safeguard against accidental cellular damage if enzymes leak from the organelle.

Functions in Cellular Degradation and Recycling

Lysosomes serve as the major catabolic compartment of the cell. They break down:

• proteins into amino acids,
• polysaccharides into monosaccharides,
• lipids into free fatty acids, and
• nucleic acids into nucleotides.

These breakdown products are transported out of the lysosome either through specific membrane transporters or via vesicular trafficking pathways. Once in the cytosol or the Golgi network, the components are reused for biosynthesis or energy production.
Lysosomes also participate in cellular clearance processes. During phagocytosis in immune cells such as macrophages, lysosomes fuse with phagosomes to degrade ingested microbes. They also participate in antigen processing, where microbial fragments are loaded onto MHC molecules for presentation to T lymphocytes. Toll-like receptors on lysosomal membranes, such as TLR7 and TLR9, assist in detecting pathogen-associated nucleic acids.
In addition, lysosomes can release their contents through lysosomal exocytosis, a mechanism important for plasma membrane repair and the secretion of certain degradation products.

Role in Autophagy and Homeostasis

Lysosomes are essential components of autophagy, a catabolic process that recycles intracellular materials. There are three major forms:

• Macroautophagy, in which cytosolic components and damaged organelles are enclosed in double-membrane autophagosomes that later fuse with lysosomes to form autolysosomes.
• Microautophagy, in which lysosomes directly engulf cytosolic material through membrane invagination.
• Chaperone-mediated autophagy, a selective process targeting proteins with a KFERQ motif, recognised by Hsc70 and delivered to the lysosomal membrane via the receptor LAMP-2A.

The resulting autolysosomes serve as hybrid degradative compartments from which basic metabolites are released back into the cytosol. These metabolites support the cell during nutrient stress and contribute to metabolic flexibility.
Lysosomes also function as nutrient sensors and metabolic regulators. The lysosomal nutrient-sensing (LYNUS) machinery, involving V-ATPase, Rag GTPases, and the mTOR complex, integrates information about nutrient levels to determine whether the cell engages in anabolic or catabolic processes. When nutrients are abundant, mTOR signalling is activated to support biosynthesis. Under starvation, lysosomal degradation is upregulated to maintain essential functions.

Degradation Pathways: Endocytosis and Autophagy

Lysosomes receive material for degradation via both endocytic and autophagic routes. Endocytosed materials travel from early endosomes to late endosomes, which often contain intraluminal vesicles forming multivesicular bodies. These compartments interact with lysosomes either through transient contacts (kiss-and-run fusion) or complete fusion. The resulting structure, an endolysosome, is the main site of degradation.
Autophagosomes and lysosomes also form transient degradative structures known as autolysosomes. Within these hybrid organelles, the majority of autophagic cargo is digested. Lysosomes then regenerate through fission events, restoring their ability to participate in further rounds of degradation.

Formation and Enzyme Targeting

Lysosomal enzymes are synthesised in the rough endoplasmic reticulum and transported to the Golgi apparatus, where they undergo modifications essential for correct targeting. A critical feature of this process is the addition of mannose-6-phosphate residues, which act as sorting markers. Vesicles carrying these hydrolases then bud from the trans-Golgi network and fuse with endosomes. As the endosome matures, its acidic environment activates the enzymes, thereby producing functional lysosomes.

Broader Biological Roles

In addition to degradation and recycling, lysosomes are involved in:

• plasma membrane repair through calcium-dependent exocytosis,
• immune activation and antigen presentation,
• metabolic regulation and energy balance,
• programmed cell death via lysosomal membrane permeabilisation, and
• maintenance of cellular homeostasis through signalling networks.