Lysosomes

1. Introduction

Lysosomes (lysosome: from the Greek: lysis; loosen and soma; body) are found in nearly all
animal and plant cells. In plant cells vacuoles can carry out lysosomal functions. Christian de
Duve, Belgian cytologist, whose laboratory in Louvain discovered lysosomes in 1955.

Lysosomes contribute to a dismantling and re-cycling facility. Many of the products of

lysosomal digestion, such as amino acids and nucleotides, are recycled back to the cell for use in
the synthesis of new cellular components. They assist with degrading material taken in from
outside the cell and life expired components from within the cell.

Recent research suggests that lysosomes are organelles that store hydrolytic enzymes in an
inactive state. The system is activated when a lysosome fuses with another particular organelle

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to form a ‘hybrid structure’ where the digestive reactions occur under acid (about pH 5.0)
conditions. From this ‘hybrid structure’ a lysosome is reformed for re-use.

Lysosomes play no part in determining which cells are eliminated. This is a function of the
processes of programmed cell death (apoptosis) and phagocytosis. Lysosomes are neither the
‘suicide bags’ nor ‘garbage disposal units’ that these evocative terms would suggest.

2. Structure and formation

Lysosomes appear initially as spherical bodies about 50-70nm in diameter but they can display
considerable variation in size and shape as a result of differences in the materials that have
been taken up for digestion. They are bounded by a single membrane. Several hundred
lysosomes may be present in a single animal cell (A human cell contains around 300 of them).

a. Lipid bilayer

They have a simple structure; they are spheres made up of a lipid bilayer that encloses fluid
that contains a variety of hydrolytic enzymes. The lipids that make up the bilayer are
phospholipids, which are molecules that have hydrophilic phosphate group heads, a glycerol
molecule, and hydrophobic fatty acid tails. Due to these differences in properties, phospholipids
naturally form double-layered membranes when placed in a solution containing water. The
phosphate group heads move to the outside of the layer, while the fatty acid tails move to the
inside of the layer to be
away from water.
b. Formation and
attachment of
enzymes

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Lysosomes are formed by
budding off of the Golgi
apparatus, and the hydrolytic
enzymes within them are
formed in the endoplasmic
reticulum. The enzymes are
tagged with the molecule
mannose-6-phosphate,
transported to the Golgi
apparatus in vesicles, and then
packaged into the lysosomes.

3. Contents

There are many different types of enzymes in lysosomes including:

1. Proteases, which hydrolyze the proteins into amino acids.

2. Lipases, which hydrolyze the lipids into fats and glycerides.
3. Amylases, which hydrolyze the polysaccharides into glucose.
4. Nucleases, which hydrolyze the nucleic acids into mononucleotides.
5. Amylases break down starches into sugars.
6. Acid phosphatase, which hydrolyses organic phosphates.

4. Types

1st

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 1. Main lysosome, which is pinched off from Golgi apparatus. It is inactive though it has
hydrolytic enzymes.
2. Secondary lysosome, which is the active lysosome. It is formed by the combination of a
main lysosome with phagosome or endosome.

2nd: Recent work suggests that there are two types of lysosomes:

 Secretory lysosomes
 Conventional ones
1. Secretory lysosomes
 Secretory lysosomes are found, although not exclusively, in different cells of the
immune system, such as T lymphocytes, derived from the hemopoietic cell line.
 Secretory lysosomes are a combination of conventional lysosomes and secretory
granules. They differ from conventional lysosomes in that they contain the particular
secretory product of the cell in which they reside.
 T lymphocytes for example contain secretory products (perforin and granzymes) that
can attack both virus infected and tumor cells. Secretory lysosome ‘combi cells’ also
contain the hydrolases, membrane proteins and have the pH regulating facility of
conventional lysosomes. The latter facility maintains an acidic environment in which the
secretory products are maintained in an inactive form.

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 The mature secretory lysosomes move within the cytoplasm to the plasma membrane.
Here they are held in ‘standby mode’ with potent ‘warhead’ secretions inactive but at
the ready. When the T lymphocyte cell is perfectly focused on the target cell, the
secretion is ‘fired’ and environmental and chemical changes, including pH, activate the
secretions before they lock on the target. This is all done with precise control of location
and timing not only to maximize effect on the target but also to minimize collateral
damage to friendly neighboring cells.
 Some conventional cells e.g. melanocytes and renal tubular cells can also carry out
regulated secretion.
 Genetically driven disorders of secretory lysosomes can lead to impaired platelet
synthesis, a type of immunodeficiency and hypopigmentation.
 Examples of secretory lysosomes:
 Lysosomes in the cytotoxic T lymphocytes and natural killer (NK) cells produce perforin
and granzymes, which ruin both viral-infected cells and tumor cells. Perforin is a pore-

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 forming protein that starts cell death. Granzymes come from the household of serine
proteases (enzymes that remove the peptide bonds of the proteins) and trigger the cell
death by apoptosis.
 Secretory lysosomes of melanocytes produce melanin. Secretory lysosomes of mast cells
produce serotonin, which is a vasoconstrictor substance and inflammatory arbitrator.
2. Conventional lysosomes
– Arrivals and meetings
 Lysosomes reside in the cell as re-usable organelles and when cell division takes place
each daughter cell receives a number of lysosomes. How this number is increased has
not yet been elucidated. It is thought that the reservoir of chemicals in the lysosome can
be ‘topped up’ by supplies from the Golgi apparatus. The chemicals are manufactured in
the endoplasmic reticulum, modified in the Golgi apparatus and transported to the
lysosomes in vesicles (sealed droplets). Modification in the Golgi apparatus includes
‘destination labelling’ at a molecular level ensuring that the vesicle is delivered to a
lysosome and not to the plasma membrane or elsewhere. The ‘label’ is returned to the
Golgi apparatus for re-use.
 Lysosomes contain about 50 enzymes that speed up the degradation of polysaccharides,
lipids, DNA and RNA. Most, but not all, lysosomal enzymes are acid hydrolases and
function at about pH 5.0.
 Acidic conditions are maintained in the lysosome by
proton pumps in the specialist membrane that
surrounds it. The proton pumps transfer hydrogen
ions from the cytosol, across the membrane and into
the interior of the lysosome.
 Material originating from 3 different sources requires
dismantling and recycling. Substrates from two of
these sources enter the cell from outside and the third
originates from within.

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  From outside the cell the process of endocytosis, including pinocytosis (cellular
drinking), admits liquids and small particles through the formation, in the plasma
membrane, of small pits that are coated with protein. These seal up to form protein
coated vesicles. Each vesicle develops to become an ‘early endosome’ and then a ‘late
endosome’.
 Also, from outside the cell phagocytosis (cellular eating) brings in relatively large
particles (generally >250 nm in size), including bacteria and cell debris. Phagocytosis can
be carried out by ‘ordinary cells’ but is mainly executed by macrophages that can
contain up to 1,000 lysosomes per cell. The structure resulting from phagocytosis is
called a phagosome.
 From inside the cell autophagosomes are responsible for removing organelles, such as
mitochondria and ribosomes, that are life expired. It is thought that a membranous
structure surrounds and encloses the life expired organelle to form an autophagosome.
This structure then fuses with a lysosome to form a ‘hybrid organelle’.
5. Endolysosomal systems:
 Research has been carried out on tracing how materials taken into the cell by
endocytosis are transported within the cell and eventually broken down. Much of the
work has centered on early and late endosomes but with a measure of caution one can
consider phagosomes, autophagosomes and late endosomes all as ‘late endosomes’ for
the purpose of trying to understand the endolysosomal system.
 There is now a considerable amount of evidence to show:
 The main site for proteolysis is not the lysosome itself but an organelle which is more
like the late endosome and contains about 20% of the available hydrolases.
 lysosomes contain about 80% of the digestive enzymes.
 lysosomes are probably storage organelles for hydrolases which they keep in an inactive
form under acidic conditions at about pH 5.0.
 lysosomes do not operate as independent organelles but meet with late endosomes to
operate as an endolysosomal system.

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  These findings have led to the development of models based on the interplay of late
endosomes and lysosomes displaying varying degrees of contact. One of these models is
called ‘kiss and run’ and the other, ‘fusion’.
1. Kiss and Run
In this model, as the name suggests, the late endosome and lysosome make contact so that
chemicals can be exchanged but after this encounter they separate fairly quickly. The
lysosome is then available to contact with another late endosome.
2. Fusion
More recent evidence has led to the ‘fusion’ hypothesis in which a late endosome and a
lysosome completely fuse together to form a ‘hybrid organelle’. During the fusion time
molecular dismantling of the endocytic load takes place. The resulting amino acids and
other molecules useful to the cell are taken by ‘transporters’ through the ‘hybrid organelle’
membrane into the cytoplasm. After dismantling and re-cycling the content of the organelle
condenses, the lysosome is reformed and moves away to form a hybrid organelle with
another late endosomes. Sometimes a small amount of residue is left. This is dealt with by
the process of exocytosis in which the residue is ejected through the plasma membrane or
it is sealed up in a pigment granule for the duration of the life of the organism.
3. Maturation system models

In both the maturation and vesicular transport models’ late endosomes develop to become a

lysosome.

i. In the maturation model an early endosome is formed from vesicles originating in the

plasma membrane combining
together. Various other vesicles
deliver and remove chemicals
until the late endosome, and
then the lysosome stage is
reached.
ii. In the vesicle transport model,
early and late endosomes are

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 considered stable separate organelles with vesicles carrying chemicals from early
endosomes to late endosomes. Late endosomes then mature to become lysosomes.
6. Mechanism of lysosomal function

Lysosomal functions include 2 mechanisms:

1. Heterophagy

Digestion of extracellular products swallowed up by the cell through endocytosis.

2. Autophagy

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 During autophagy, sequestration begins with the formation of a phagophore that expands
into a double-membrane autophagosome while surrounding a portion of the cytoplasm.
The autophagosome may fuse with an endosome (the product of endocytosis), which is a
form of heterophagy. The product of the endosome-autophagosome fusion is called an
amphisome. The completed autophagosome or amphisome fuses with a lysosome, which
supplies acid hydrolases. The enzymes in the resulting compartment, an autolysosome,
break down the inner membrane from the autophagosome and degrade the cargo. The
resulting macromolecules are released and recycled in the cytosol.

7. Particular functions of lysosomes

 Destruction of macromolecules

Macromolecules are swallowed up by the cell by methods of endocytosis (phagocytosis,

pinocytosis or receptor- moderated endocytosis). The macromolecules such as bacteria,
swallowed up by the cell through phagocytosis are called phagosomes or vacuoles. The other
macromolecules taken inside through pinocytosis or receptor-mediated endocytosis are
called endosomes. The main lysosome merges with the phagosome or endosome to form the

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secondary lysosome. The pH in the secondary lysosome ends up being acidic and the lysosomal
enzymes are triggered. The bacteria and the other macromolecules are absorbed and broken
down by these enzymes. The secondary lysosome consisting of these broken-down waste
products moves through cytoplasm and merges with cell membrane. Now the waste products
are gotten rid of by exocytosis.

 Destruction of damaged organelles

The rough endoplasmic reticulum covers itself around the damaged organelles like
mitochondria and form the vacuoles called autophagosomes. One main lysosome merge with
one autophagosome to form the secondary lysosome. The enzymes in the secondary lysosome
are triggered. Now, these enzymes absorb the contents of autophagosome.

 Elimination of excess secretory products in the cells

Lysosomes in the cells of the secretory glands eliminate the excess secretory products by
breaking down the secretory granules.

 Secretory function – secretory lysosomes

These are Found in in the cells of immune system (cytotoxic T lymphocytes and natural
killer (NK) cells) which attacks on viral infected cells and tumor cells.
8. Lipofuscin granules

Fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal

digestion. Lipofuscin is sometimes called "wear-and-tear pigment", since the amount increases
over time (i.e., with advancing age) in cells
like hepatocytes and neurons which are both
permanent (not routinely replenished) and
metabolically active.

9. Storage disease
 Lysosomal storage diseases are
genetic disorders in which a
genetic mutation affects the activity

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 of one or more of the acid hydrolases. In such diseases, the normal metabolism of
specific macromolecules is blocked and the macromolecules accumulate inside the
lysosomes, causing severe physiological damage or deformity.
 There are around 50 different LSDs. Each type of LSD is rare, occurring in less than 1 in
100,000 births; however, as a group, LSDs occur in 1 in 5,000-10,000. LSDs usually occur
when a person is deficient in one enzyme that breaks down large molecules like proteins
or lipids. Because the enzyme is lacking, the large molecules cannot be broken down,
and they eventually build up within the cell and kill it.
 Most LSDs are inherited in an autosomal recessive pattern. This means that it can be
masked by a copy of an allele without the mutation (a dominant allele) and is caused by
a mutation on one of the autosomal chromosomes, which are all chromosomes except
the sex chromosomes X and Y.
A. Tay-Sachs disease is an example of a well-known LSD that is recessively inherited. Due
to insufficient function of the enzyme hexosaminidase A, glycolipids build up in the brain
and interfere with normal functioning. This causes nerve cells to break down, and
physical and mental functioning to decline. There is no cure, and death usually occurs by
age four.

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B. Fabry disease is rare, occurring in 1 in 40,000-120,000 live births. People with Fabry
disease are deficient in the enzyme alpha galactosidase A, which causes the glycolipid
globotriaosylceramide to build up within the body. Symptoms include fatigue, burning
pain in the extremities or full body pain, tinnitus, nausea, cardiac and kidney
complications, and papules on the skin called angiokeratomas. The mutation that causes
Fabry disease is located on the X-chromosome, but females with only one copy of the
mutated gene also show symptoms. Since men only have one X chromosome, their
symptoms tend to be more severe. Life expectancy for those with this disease in the
United States is 58.2 for males and 75.4 for females.
C. Hurler’s syndrome, also called Gargoylism, or Mucopolysaccharidosis I, one of several
rare genetic disorders involving a defect in the metabolism of mucopolysaccharides, the
class of polysaccharides that bind water
to unite cells and to lubricate joints.
Onset of the syndrome is in infancy or
early childhood, and the disease occurs
with equal frequency in both sexes.
Affected individuals exhibit
severe mental retardation, clouding of
the corners of the eyes, deafness,
hirsutism (hairiness),

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enlarged liver and spleen, dwarfism with hunched back, short limbs and clawed hands, a
large head with wide-set eyes, heavy brow ridges and deep bridge of nose, and poorly
formed teeth. The disorder is identifiable within two years of birth; such children
require institutional care and usually do not live beyond adolescence. Death most often
results from heart failure, which is attributable to infiltration of heart muscle and
coronary vessels with mucopolysaccharides.

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 References

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https://www.britannica.com/science/Hurler-syndrome
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