Lysosome

A lysosome is a membrane-bound organelle found in many animal cells

and most plant cells. They are spherical vesicles that contain hydrolytic
Cell biology
enzymes that can break down many kinds of biomolecules. A lysosome The animal cell
has a specific composition, of both its membrane proteins, and its
lumenal proteins. 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 signaling,
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 the
cell and obsolete components inside the cell. Material from outside the Components of a typical animal cell:
cell is taken-up through endocytosis, while material from the inside of
the cell is digested through autophagy. Their sizes can be very different 1. Nucleolus
—the largest ones can be more than 10 times the size of the smallest 2. Nucleus
ones.[3] They were discovered and named by Belgian biologist Christian 3. Ribosome (little dots)
de Duve, who eventually received the Nobel Prize in Physiology or
4. Vesicle
Medicine in 1974.
5. Rough endoplasmic reticulum
Lysosomes are known to contain more than 60 different enzymes.[4][5] 6. Golgi apparatus (or "Golgi body")
Enzymes of the lysosomes are synthesised in the rough endoplasmic 7. Cytoskeleton
reticulum. The enzymes are imported from the Golgi apparatus in small
8. Smooth endoplasmic reticulum
vesicles, which fuse with larger acidic vesicles. Enzymes destined for a
lysosome are specifically tagged with the molecule mannose 6-
9. Mitochondrion
[6][7]
phosphate, so that they are properly sorted into acidified vesicles. 10. Vacuole
11. Cytosol (fluid that contains organelles,
Synthesis of lysosomal enzymes is controlled by nuclear genes.
comprising the cytoplasm)
Mutations in the genes for these enzymes are responsible for more than
12. Lysosome
30 different human genetic disorders, which are collectively known as
lysosomal storage diseases. These diseases result from an accumulation 13. Centrosome
of specific substrates, due to the inability to break them down. These 14. Cell membrane
genetic defects are related to several neurodegenerative disorders,
cancers, cardiovascular diseases, and ageing-related diseases.[8][9]

Lysosomes should not be confused withliposomes, or with micelles.

Contents
Discovery
Function and structure
Formation
Pathogen entry
Clinical significance
Lysosomotropism
 Controversy in botany
Etymology and pronunciation
See also
References
External links

Discovery
Lysosomes digest materials taken
Christian de Duve, the chairman of the Laboratory of Physiological Chemistry at the into the cell and recycle intracellular
Catholic University of Louvain in Belgium, had been studying the mechanism of materials. Step one shows material
action of a pancreatic hormone insulin in liver cells. By 1949, he and his team had entering a food vacuole through the
focused on the enzyme called glucose 6-phosphatase, which is the first crucial plasma membrane, a process known
as endocytosis. In step two a
enzyme in sugar metabolism and the target of insulin. They already suspected that
lysosomes within an active hydrolytic
this enzyme played a key role in regulating blood sugar levels. However, even after
enzyme comes into picture as the
a series of experiments, they failed to purify and isolate the enzyme from the cellular food vacuole moves away from the
extracts. Therefore, they tried a more arduous procedure of cell fractionation, by plasma membrane. Step three
which cellular components are separated based on their sizes usingcentrifugation. consists of the lysosome fusing with
the food vacuole and hydrolytic
They succeeded in detecting the enzyme activity from the microsomal fraction. This enzymes entering the food vacuole.
was the crucial step in the serendipitous discovery of lysosomes. To estimate this In the final step, step four, hydrolytic
enzyme activity, they used that of standardised enzyme acid phosphatase, and found enzymes digest the food particles.
SOURCE:Holtzclaw, Fred W., et al.
that the activity was only 10% of the expected value. One day, the enzyme activity
AP* Biology: to Accompany Biology,
of purified cell fractions which had been refrigerated for five days was measured.
Campbell, Reece, 8e AP* Edition.
Surprisingly, the enzyme activity was increased to normal of that of the fresh Pearson Benjamin Cummings, 2008.
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."[10]

It became clear that this enzyme from the cell fraction came from membranous
fractions, which were definitely cell organelles, and in 1955 De Duve named them
"lysosomes" to reflect their digestive properties.[11] 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.[12][13] 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.[14] However, it has since been TEM views of various vesicular
concluded that they only play a minor role incell death.[15] compartments. Lysosomes are
denoted by "Ly". They are dyed dark
due to their acidity; in the center of
Function and structure the top image, a Golgi Apparatus can
be seen, distal from the cell
membrane relative to the lysosomes.
Lysosomes contain a variety of enzymes, enabling the cell to break down various biomolecules it engulfs, including peptides, nucleic
acids, carbohydrates, and lipids (lysosomal lipase). 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 with phagosomes, they are able to conduct autophagy, clearing out damaged structures.
Similarly, they are able to break-down virus particles or bacteria inphagocytosis of macrophages.

The size of lysosomes varies from 0.1 μm to 1.2 μm.[16] With a pH ranging from 4.5 to 5.0, 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 hydrolases that 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-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.[17][18]

It sources its versatile capacity for degradation by import of enzymes with specificity for dif
ferent substrates; cathepsins are the major
class of hydrolytic enzymes, while lysosomal alpha-glucosidaseis responsible for carbohydrates, and lysosomal acid phosphatase is
necessary to release phosphate groups of phospholipids.

Formation
Many components of animal cells are recycled by transferring them inside or
embedded in sections of membrane. For instance, in endocytosis (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.[19][20]

The production of lysosomal proteins suggests one method of lysosome sustainment.

Lysosomal protein genes are transcribed in the nucleus. mRNA transcripts exit the
nucleus into the cytosol, where they are translated by ribosomes. The nascent The lysosome is shown in purple, as
peptide chains are translocated into the rough endoplasmic reticulum, where they are an endpoint in Endocytotic sorting.
modified. Lysosomal soluble proteins exit the endoplasmic reticulum via CLN8- AP2 is necessary for vesicle
mediated recruitment in COPII-coated vesicles[21] and enter the Golgi apparatus, formation, whereas the Mannose-6-
receptor is necessary for sorting
where a specific lysosomal tag, mannose 6-phosphate, is added to the peptides. The
Hydrolase into the Lysosome's
presence of these tags allow for binding to mannose 6-phosphate receptors in the
lumen.
Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles
destined for the lysosomal system.[22]

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 6-phosphate
receptors. The enzymes are packed into vesicles for further transport to established lysosomes.[22] 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.[19]

Pathogen entry
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.[23] In addition, AB5 toxins
such as cholera hijack the endosomal pathway while evading lysosomal
degradation.[23]

Clinical significance
Lysosomes are involved in a group of geneticallyinherited deficiencies, or mutations
called lysosomal storage diseases (LSD), inborn errors of metabolism caused by a
dysfunction of one of the enzymes. The rate of incidence is estimated to be 1 in
5,000 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 acid 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.[8] 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.[24][25]

There is no direct medical treatment to cure LSDs.[26] 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.[27][28] As
of 2017, enzyme replacement therapy is available for treating 8 of the 50-60 known
LDs.[29]

The most severe and rarely found, lysosomal storage disease is inclusion cell
disease.[30]

Metachromatic leukodystrophyis another lysosomal storage disease that also affects

sphingolipid metabolism.
Cholera gaining entry into a cell via
endocytosis.
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[31] , "acid trapping" or "proton pump" effect [32] . The amount of accumulation of lysosomotropic compounds
[33]
may be estimated using a cell-based mathematical model.
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,[34] levomepromazine,[35] and amantadine.[36] However, high
tissue concentrations and long elimination half-lives are explained also by lipophilicity and absorption of drugs to fatty tissue
[37][38]
structures. Important lysosomal enzymes, such as acid sphingomyelinase, may be inhibited by lysosomally accumulated drugs.
Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[39] 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.[40] 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.[41][42]

Controversy in botany
By scientific convention, the term lysosome is applied to these vesicular organelles only in animals, and the term vacuole is applied
to those in plants, fungi and algae (some animal cells also have vacuoles). Discoveries in plant cells since the 1970s started to
challenge this definition. Plant vacuoles are found to be much more diverse in structure and function than previously thought.[43][44]
Some vacuoles contain their own hydrolytic enzymes and perform the classic lysosomal activity, which is autophagy.[45][46][47]
These vacuoles are therefore seen as fulfilling the role of the animal lysosome. Based on de Duve's description that "only when
considered as part of a system involved directly or indirectly in intracellular digestion does the term lysosome describe a
physiological unit", some botanists strongly argued that these vacuoles are lysosomes.[48] However, this is not universally accepted
as the vacuoles are strictly not similar to lysosomes, such as in their specific enzymes and lack of phagocytic functions.[49] Vacuoles
do not have catabolic activity and do not undergo exocytosis as lysosomes do.[50]

Etymology and pronunciation

The word lysosome (/ˈlaɪsoʊsoʊm/, /ˈlaɪzəzoʊm/) is New Latin that uses the combining forms lyso- (referring to lysis and derived
from the Latin lysis, meaning "to loosen", via Ancient Greek λύσις [lúsis]), and -some, from soma, "body", yielding "body that lyses"
or "lytic body". The adjectival form is lysosomal. The forms *lyosome and *lyosomal are much rarer; they use the lyo- form of the
prefix but are often treated by readers and editors as mere unthinking replications of typos, which has no doubt been true as often as
not.

See also
Peroxisome
Cathelicidin
Antimicrobial peptides
Innate immune system

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External links
This article incorporatespublic domain material from the NCBI document "Science Primer".
3D structures of proteins associated with lysosome membrane
Hide and Seek Foundation For Lysosomal Research
Lysosomal Disease Network, a research consortium funded by the NIH through its NCA TS/Rare Diseases Clinical
Research Network
Self-Destructive Behavior in Cells May Hold Key to a Longer Life
Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
Animation showing how lysosomes are made, and their function

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