Lysosome

Cell biology

Animal cell diagram

Components of a typical animal cell:

1. Nucleolus

2. Nucleus

3. Ribosome (dots as part of 5)

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; with which,

comprises cytoplasm)

12. Lysosome

13. Centrosome

14. Cell membrane

A lysosome (/ˈlaɪsəˌsoʊm/) is a membrane-bound organelle found in many

animal cells.[1] They are spherical vesicles that contain hydrolytic enzymes that digest
many kinds of biomolecules. A lysosome has a specific composition, of both
its membrane proteins and its lumenal proteins. The lumen's pH (~4.5–5.0)[2] is
optimal for the enzymes involved in hydrolysis, analogous to the activity of
the stomach. Besides degradation of polymers, the lysosome is involved in cell
processes of secretion, plasma membrane repair, apoptosis, cell signaling,
and energy metabolism.[3]
 Lysosomes digest materials taken into the cell and
recycle intracellular materials. Step one shows material entering a food vacuole
through the plasma membrane, a process known as endocytosis. In step two a
lysosome with an active hydrolytic enzyme comes into the picture as the food
vacuole moves away from the plasma membrane. Step three consists of the
lysosome fusing with the food vacuole and hydrolytic enzymes entering the food
vacuole. In the final step, step four, hydrolytic enzymes digest the food particles. [4]
Lysosomes are degradative organelles that act as the waste disposal system of the
cell by digesting used materials in the cytoplasm, from both inside and outside the
cell. Material from outside the cell is taken up through endocytosis, while material
from the inside of the cell is digested through autophagy.[5] The sizes of the
organelles vary greatly—the larger ones can be more than 10 times the size of the
smaller ones.[6] They were discovered and named by Belgian biologist Christian de
Duve, who eventually received the Nobel Prize in Physiology or Medicine in 1974.

Lysosomes contain more than 60 different enzymes, and have more than 50
membrane proteins.[7][8] Enzymes of the lysosomes are synthesized in the rough
endoplasmic reticulum and exported to the Golgi apparatus upon recruitment by a
complex composed of CLN6 and CLN8 proteins.[9][10] The enzymes are transported
from the Golgi apparatus to lysosomes in small vesicles, which fuse with larger
acidic vesicles. Enzymes destined for a lysosome are tagged with the
molecule mannose 6-phosphate, so that they are properly sorted into acidified
vesicles.[11][12]

In 2009, Marco Sardiello and co-workers discovered that the synthesis of most
lysosomal enzymes and membrane proteins is controlled by transcription factor EB
(TFEB), which promotes the transcription of nuclear genes.[5][13] Mutations in the
genes for these enzymes are responsible for more than 50 different human genetic
disorders collectively known as lysosomal storage diseases. These diseases result
in an accumulation of specific substrates, due to the inability to break them down.
These genetic defects are related to several neurodegenerative disorders,
cancers, cardiovascular diseases, and aging-related diseases.[14][15][16]

Etymology and pronunciation[edit]

The word lysosome (/ˈlaɪsoʊsoʊm/, /ˈlaɪzəzoʊm/) is Neo-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.
Discovery[edit]

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 lysosome .
Christian de Duve, at the Laboratory of Physiological Chemistry at the Catholic
University of Louvain in Belgium, had been studying the mechanism of action
of 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 the standardized 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."[17]

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.[18] 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.[19][20] 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.[21] However, it has since been
concluded that they only play a minor role in cell death.[22]

Function and structure[edit]

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
in phagocytosis of macrophages.

The size of lysosomes varies from 0.1 μm to 1.2 μm.[23] With a pH ranging from ~4.5–
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.[24][25]

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 is responsible for carbohydrates, and lysosomal
acid phosphatase is necessary to release phosphate groups of phospholipids.

Recent research also indicates that lysosomes can act as a source of intracellular
calcium.[26]

Formation[edit]
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, in endocytosis (more
specifically, macropinocytosis), a portion of the cell's plasma membrane pinches off
to form vesicles 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 from endosomes.[27][28]

The production of lysosomal proteins suggests one method of lysosome

sustainment. Lysosomal protein genes are transcribed in the nucleus in a process
that is controlled by transcription factor EB (TFEB).[13] mRNA transcripts exit the
nucleus into the cytosol, where they are translated by ribosomes. The nascent
peptide chains are translocated into the rough endoplasmic reticulum, where they
are modified. Lysosomal soluble proteins exit the endoplasmic reticulum via COPII-
coated vesicles after recruitment by the EGRESS complex (ER-to-Golgi relaying
of enzymes of the lysosomal system), which is composed
of CLN6 and CLN8 proteins.[9][10] COPII vesicles then deliver lysosomal enzymes to
the Golgi apparatus, where 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.[29]

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.[29] 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.[27]

Pathogen entry[edit]
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.[30] In
addition, AB5 toxins such as cholera hijack the endosomal pathway while evading
lysosomal degradation.[30]

Clinical significance[edit]
Lysosomes are involved in a group of genetically inherited 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.
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.[14] 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.[31][32]

There is no direct medical treatment to cure LSDs.[33] 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.[34][35] As of
2017, enzyme replacement therapy is available for treating 8 of the 50-60 known
LDs.[36]

The most severe and rarely found, lysosomal storage disease is inclusion cell
disease.[37]

Metachromatic leukodystrophy is another lysosomal storage disease that also

affects sphingolipid metabolism.

Dysfunctional lysosome activity is also heavily implicated in the biology of aging, and
age-related diseases such as Alzheimer's, Parkinson's, and cardiovascular
disease.[16][38]