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Lysosome
Cell biology
The animal cell
Components of a typical animal cell:
1. Nucleolus
2. Nucleus
3. Ribosome (little dots)
4. Vesicle
5. Rough endoplasmic reticulum
6. Golgi apparatus (or "Golgi body")
7. Cytoskeleton
8. Smooth endoplasmic reticulum
9. Mitochondrion
10. Vacuole
11. Cytosol (fluid that contains organelles, comprising
the cytoplasm)
12. Lysosome
13. Centrosome
14. Cell membrane
A lysosome is a membrane-bounded organelle found in most animal cells. They are
spherical vesicles which contain hydrolyticenzymes that can break down virtually all kinds
of biomolecules. Simply stated, a lysosome is a type of vesicle with specific composition,
of both its membrane proteins, and proteins of its lumen. The lumen's pH (4.5 - 5.0)[1] is
optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach.
Besides degradation of polymers, the lysosome is involved in various cell processes,
including secretion, plasma membrane repair, cell signalling, and energy metabolism.[2]
The lysosomes also act as the waste disposal system of the cell by digesting unwanted
materials in the cytoplasm, both from outside of the cell and obsolete components inside
the cell. Material from the outside of the cell is taken-up throughendocytosis, while
material from the inside of the cell is digested through autophagy. Their sizes can be very
different—the biggest ones can be more than 10 times bigger than the smallest
ones.[3] They were discovered and named by Belgian biologistChristian de Duve, who
eventually received the Nobel Prize in Physiology or Medicine in 1974.
Lysosomes are known to contain more than 50 different enzymes. Enzymes of the
lysosomes are synthesised in the rough endoplasmic reticulum. The enzymes are
imported from the Golgi apparatus in small vesicles, which fuse with larger acidic
vesicles. Enzymes destined for a lysosome are specifically tagged with the
molecule mannose 6-phosphate, so that they are properly sorted into acidified
vesicles.[citation needed]
Synthesis of lysosomal enzymes is controlled by nuclear genes. Mutations in the genes
for these enzymes are responsible for more than 30 different human genetic diseases,
which are collectively known as lysosomal storage diseases. These diseases result from
an accumulation of specific substrates, due to the inability to break them down. These
genetic defects are related to several neurodegenerative
disorders, cancer, cardiovascular diseases, and ageing-related diseases.[4][5]

Discovery[
TEM views of various vesicular compartments. Lysosomes are denoted by "Ly". They are dyed
dark due to their acidity; in the center of the top image, a Golgi Apparatus can be seen, distal from
the cell membrane relative to the lysosomes.
Christian de Duve, then chairman of the Laboratory of Physiological Chemistry at
the Catholic University of Louvain in Belgium, had been studying the mechanism of
action of a pancreatic hormone insulin in liver cells. By 1949, he and his team had
focused on the enzyme called glucose 6-phosphatase, which is the first crucial enzyme in
sugar metabolism and the target of insulin. They already suspected that this enzyme
played a key role in regulating blood sugar levels. However, even after a series of
experiments, they failed to purify and isolate the enzyme from the cellular extracts.
Therefore, they tried a more arduous procedure of cell fractionation, by which cellular
components are separated based on their sizes using centrifugation.
They succeeded in detecting the enzyme activity from the microsomal fraction. This was
the crucial step in the serendipitous discovery of lysosomes. To estimate this enzyme
activity, they used that of standardised enzyme acid phosphatase, and found that the
activity was only 10% of the expected value. One day, the enzyme activity of purified cell
fractions which had been refrigerated for five days was measured. Surprisingly, the
enzyme activity was increased to normal of that of the fresh sample. The result was the
same no matter how many times they repeated the estimation, and led to the conclusion
that a membrane-like barrier limited the accessibility of the enzyme to its substrate, and
that the enzymes were able to diffuse after a few days (and react with their substrate).
They described this membrane-like barrier as a "saclike structure surrounded by a
membrane and containing acid phosphatase."[6]
It became clear that this enzyme from the cell fraction came from a membranous
fractions, which were definitely cell organelles, and in 1955 De Duve named them
"lysosomes" to reflect their digestive properties.[7] The same year, Alex B. Novikoff from
the University of Vermont visited de Duve´s laboratory, and successfully obtained the
first electron micrographs of the new organelle. Using a staining method for acid
phosphatase, de Duve and Novikoff confirmed the location of the hydrolytic enzymes of
lysosomes using light and electron microscopic studies.[8][9] de Duve won the Nobel Prize
in Physiology or Medicine in 1974 for this discovery.
Originally, De Duve had termed the organelles the "suicide bags" or "suicide sacs" of the
cells, for their hypothesized role in apoptosis.[10]However, it has since been concluded
that they only play a minor role in cell death.[11]
Function and structure[
Lysosomes contain a variety of enzymes in order to be able to break down the variety of
biomolecules engulfed by the cell, including peptides, nucleic acids, carbohydrates,
andlipids. The enzymes responsible for this hydrolysis require an acidic environment for
optimal activity.
In addition to being able to break down polymers, lysosomes are capable of fusing with
other organelles & digesting large structures or cellular debris; through cooperation
withphagosomes, they are able to conduct autophagy, clearing out damaged structures.
Similarly, they are able to break-down virus particles or bacteria
in phagocytosis ofmacrophages.
The size of lysosomes varies from 0.1–1.2 μm.[12] At pH 4.5 - 5, the interior of the
lysosomes is acidic compared to the slightly basic cytosol (pH 7.2). The lysosomal
membrane protects the cytosol, and therefore the rest of the cell, from the degradative
enzymes within the lysosome. The cell is additionally protected from any lysosomal
acid hydrolasesthat drain into the cytosol, as these enzymes are pH-sensitive and do not
function well or at all in the alkaline environment of the cytosol. This ensures that
cytosolic molecules and organelles are not destroyed in case there is leakage of the
hydrolytic enzymes from the lysosome.
The lysosome maintains its pH differential by pumping in protons (H+ ions) from the
cytosol across the membrane via proton pumps and chloride ion channels. Vacuolar H+ATPases are responsible for transport of protons, while the counter transport of chloride
ions is performed by ClC-7 Cl−/H+ antiporter. In this way a steady acidic environment is
maintained.[13][14]
It sources its versatile capacity for degradation by import of enzymes with specificity for
different substrates; cathepsins are the major class of hydrolytic enzymes, while
lysosomal alpha-glucosidase (GAA) is responsible for carbohydrates, and ACP2 is
necessary to release phosphate groups of phospholipids.
Formation[
The Lysosome is shown in purple, as an endpoint in Endocytotic sorting. AP2 is necessary for
vesicle formation, whereas the Mannose-6-receptor is necessary for sorting Hydrolase into the
Lysosome's lumen.
Many components of animal cells are recycled by transferring them inside or embedded
in sections of membrane. For instance, inendocytosis (more
specifically, macropinocytosis), a portion of the cell’s plasma membrane pinches off to
form a vesicle that will eventually fuse with an organelle within the cell. Without active
replenishment, the plasma membrane would continuously decrease in size. It is thought
that lysosomes participate in this dynamic membrane exchange system and are formed
by a gradual maturation process fromendosomes.[15][16]
The production of lysosomal proteins suggests one method of lysosome sustainment.
Lysosomal protein genes are transcribed in thenucleus. mRNA transcripts exit the
nucleus into the cytosol, where they are translated by ribosomes. The nascent peptide
chains aretranslocated into the rough endoplasmic reticulum, where they are modified.
Upon exiting the endoplasmic reticulum and entering theGolgi apparatus via vesicular
transport, a specific lysosomal tag, mannose 6-phosphate, is added to the peptides. The
presence of these tags allow for binding to mannose 6-phosphate receptors in the Golgi
apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for
the lysosomal system.[17]
Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with a late
endosome, a relatively acidic organelle with an approximate pH of 5.5. This acidic
environment causes dissociation of the lysosomal enzymes from the mannose 6phosphate receptors. The enzymes are packed into vesicles for further transport to
established lysosomes.[17] The late endosome itself can eventually grow into a mature
lysosome, as evidenced by the transport of endosomal membrane components from the
lysosomes back to the endosomes.[15]
Cholera gaining entry into a cell via endocytosis.
As the endpoint of endocytosis, the lysosome also acts as a safeguard in preventing
pathogens from being able to reach the cytoplasm before being degraded. Pathogens
often hijack endocytotic pathways such as pinocytosis in order to gain entry into the cell.
The lysosome prevents easy entry into the cell by hydrolyzing the biomolecules of
pathogens necessary for their replication strategies; reduced Lysosomal activity results in
an increase in viral infectivity, including HIV.[18] In addition, AB5 toxins such
as cholera hijack the endosomal pathway while evading lysosomal degradation.[18]
Disease[
Lysosomes are responsible for a group of genetically inherited disorders called lysosomal
storage diseases (LSD). They are a type ofinborn errors of metabolism caused by
malfunction of one of the enzymes. The rate of incidence is estimated to be 1 in 5,000
live births, and the true figure expected to be higher as many cases are likely to be
undiagnosed or misdiagnosed. The primary cause is deficiency of an acidic hydrolase (a
hydrolase which functions best in acidic environments). Other conditions are due to
defects in lysosomal membrane proteins that fail to transport the enzyme, non-enzymatic
soluble lysosomal proteins. The initial effect of such disorders is accumulation of specific
macromolecules or monomeric compounds inside the endosomal–autophagic–lysosomal
system.[4] This results in abnormal signaling pathways, calcium homeostasis, lipid
biosynthesis and degradation and intracellular trafficking, ultimately leading to
pathogenetic disorders. The organs most affected are brain, viscera, bone
and cartilage.[19][20]
There is no direct medical treatment to cure LSDs.[21] The most common LSD
is Gaucher's disease, which is due to deficiency of the enzyme glucocerebrosidase.
Consequently, the enzyme substrate, the fatty acid glucosylceramide accumulates,
particularly in white blood cells, which in turn affects spleen, liver, kidneys, lungs, brain
and bone marrow. The disease is characterized by bruises, fatigue, anaemia, low blood
platelets, osteoporosis, and enlargement of the liver and spleen.[22][23]
Metachromatic leukodystrophy is another lysosomal storage disease that also
affects sphingolipid metabolism.
Lysosomotropism[
Weak bases with lipophilic properties accumulate in acidic intracellular compartments like
lysosomes. While the plasma and lysosomal membranes are permeable for neutral and
uncharged species of weak bases, the charged protonated species of weak bases do not
permeate biomembranes and accumulate within lysosomes. The concentration within
lysosomes may reach levels 100 to 1000 fold higher than extracellular concentrations.
This phenomenon is called "lysosomotropism"[24] or "acid trapping". The amount of
accumulation of lysosomotropic compounds may be estimated using a cell-based
mathematical model.[25]
A significant part of the clinically approved drugs are lipophilic weak bases with
lysosomotropic properties. This explains a number of pharmacological properties of these
drugs, such as high tissue-to-blood concentration gradients or long tissue elimination
half-lifes; these properties have been found for drugs such
as haloperidol,[26] levomepromazine,[27] and amantadine.[28] However, high tissue
concentrations and long elimination half-lives are explained also by lipophilicity and
absorption of drugs to fatty tissue structures. Important lysosomal enzymes, such as acid
sphingomyelinase, may be inhibited by lysosomally accumulated drugs.[29][30] Such
compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[31] and
include for example fluoxetine, sertraline, or amitriptyline.
Ambroxol is a lysosomotropic drug of clinical use to treat conditions of productive cough
for its mucolytic action. Ambroxol triggers the exocytosis of lysosomes via neutralization
of lysosomal pH and calcium release from acidic calcium stores.[32] Presumably for this
reason,Ambroxol was also found to improve cellular function in some disease of
lysosomal origin such as Parkinson's or lysosomal storage disease.[33][34]