Wednesday 24 September 2003
Definition: Lysosomes are dynamic organelles that receive and degrade macromolecules from the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways.
Lysosomes are organelles that contain digestive enzymes (acid hydrolases). They digest excess or worn out organelles, food particles, and engulfed viruses or bacteria. The membrane surrounding a lysosome prevents the digestive enzymes inside from destroying the cell. Lysosomes fuse with vacuoles and dispense their enzymes into the vacuoles, digesting their contents. They are built in the Golgi apparatus.
The name lysosome derives from the Greek words lysis, which means dissolution or destruction, and soma, which means body. They are frequently nicknamed "suicide-bags" or "suicide-sacs" by cell biologists due to their role in autolysis. Lysosomes were discovered by the Belgian cytologist Christian de Duve in 1949.
The word "lysosome" is Latin for "kill body." Lysosomes are organelles produced by the Golgi apparatus that contain powerful protein digesting enzymes. Lysosomes are responsible for the breakdown and absorption of materials taken in by the cell.
Lysosomes are key components of the "intracellular digestive tract." They contain a battery of hydrolytic enzymes, which have two special properties. First, they can function in the acid milieu of the lysosomes. Second, these enzymes constitute a special category of secretory proteins that, in contrast to most others, are destined for secretion not into the extracellular fluids but into an intracellular organelle. This latter characteristic requires special processing within the Golgi apparatus, which is reviewed briefly.
The lysosomes are used for the digestion of macromolecules from phagocytosis (ingestion of other dying cells or larger extracellular material), endocytosis (where receptor proteins are recycled from the cell surface), and autophagy (where old or unneeded organelles or proteins, or microbes which have invaded the cytoplasm are delivered to the lysosome). Autophagy may also lead to autophagic cell death, a form of programmed self-destruction, or autolysis, of the cell, which means that the cell is digesting itself.
Other functions include digesting foreign bacteria (or other forms of waste) that invade a cell and helping repair damage to the plasma membrane by serving as a membrane patch, sealing the wound. Lysosomes also do much of the cellular digestion required to digest tails of tadpoles and to remove the web from the fingers of a 3-6 month old fetus. This process of programmed cell death is called apoptosis.
Live-cell imaging has shown that fusion with lysosomes occurs by both transient and full fusion events, and yeast genetics and mammalian cell-free systems have identified much of the protein machinery that coordinates these fusion events.
Many pathogens that hijack the endocytic pathways to enter cells have evolved mechanisms to avoid being degraded by the lysosome. However, the function of lysosomes is not restricted to protein degradation: they also fuse with the plasma membrane during cell injury, as well as having more specialized secretory functions in some cell types.
At pH 4.8, the interior of the lysosomes is more acidic than the cytosol (pH 7.2). The lysosome’s single membrane stabilizes the low pH by pumping in protons (H+) from the cytosol via proton pumps and chloride ion channels. The membrane also protects the cytosol, and therefore the rest of the cell, from the degradative enzymes within the lysosome. For this reason, should a lysosome’s acid hydrolases leak into the cytosol, their potential to damage the cell will be reduced, because they will not be at their optimum pH.
Some important enzymes in these are:
Lipase, which digests lipids
Carbohydrases, which digest carbohydrates (e.g., sugars)
Proteases, which digest proteins
Nucleases, which digest nucleic acids
Phosphatases, which digest phosphoric acid monoesters.
Lysosomal enzymes are synthesized in the cytosol and the endoplasmic reticulum, where they receive a mannose-6-phosphate tag that targets them for the lysosome.
Aberrant lysosomal targeting causes inclusion-cell disease (mucolipidosis type 2), whereby enzymes do not properly reach the lysosome, resulting in accumulation of waste within these organelles.
Similar to all other secretory proteins, lysosomal enzymes (or acid hydrolases, as they are sometimes called) are synthesized in the endoplasmic reticulum and transported to the Golgi apparatus.
Within the Golgi complex, they undergo a variety of post-translational modifications, of which one is worthy of special note. This modification involves the attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains.
The phosphorylated mannose residues may be viewed as an "address label" that is recognized by specific receptors found on the inner surface of the Golgi membrane. Lysosomal enzymes bind to these receptors and are thereby segregated from the numerous other secretory proteins within the Golgi.
Subsequently, small transport vesicles containing the receptor-bound enzymes are pinched off from the Golgi and proceed to fuse with the lysosomes. Thus, the enzymes are targeted to their intracellular abode, and the vesicles are shuttled back to the Golgi.
The lysosomal acid hydrolases catalyze the breakdown of a variety of complex macromolecules. These large molecules may be derived from the metabolic turnover of intracellular organelles (autophagy), or they may be acquired from outside the cells by phagocytosis (heterophagy).
lysosomal membrane proteins
There are a number of diseases that are caused by the malfunction of the lysosomes or one of their digestive proteins. These are caused by a defective or missing digestive protein, which leads to the accumulation of substrates within the cell, impairing metabolism. For example, Tay-Sachs disease, Pompe disease, Fabry disease or Wolman disease are ’lysosomal diseases’.
Lysosomal storage diseases can be classified as:
lipid storage disorders
Fehrenbacher N, Jaattela M. Lysosomes as targets for cancer therapy. Cancer Res. 2005 Apr 15;65(8):2993-5. PMID: 15833821
Huizing M, Gahl WA. Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr Mol Med. 2002 Aug;2(5):451-67. PMID: 12125811
Andrews NW. Regulated secretion of conventional lysosomes. Trends Cell Biol. 2000 Aug;10(8):316-21. PMID: 10884683