A lysosome () is a
membrane-bound organelle
In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
found in many animal
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s. They are spherical
vesicles
Vesicle may refer to:
; In cellular biology or chemistry
* Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane
* Synaptic vesicle
; In human embryology
* Vesicle (embryology), bulge-like features o ...
that contain
hydrolytic
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s that can break down many kinds of
biomolecule
A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include large ...
s. A lysosome has a specific composition, of both its
membrane protein
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
s, and its
lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion,
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
repair,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
,
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
, and
energy metabolism
Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of biological research that includes the study of the transformation of energy in living organisms and the study of ...
.
![Lysosomes Digestion](https://upload.wikimedia.org/wikipedia/commons/6/65/Lysosomes_Digestion.svg)
Lysosomes act as the waste disposal system of the cell by digesting used materials in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, from both inside and outside the cell. Material from outside the cell is taken up through
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
, while material from the inside of the cell is digested through
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
. The sizes of the organelles vary greatly—the larger ones can be more than 10 times the size of the smaller ones. They were discovered and named by Belgian biologist
Christian de Duve
Christian René Marie Joseph, Viscount de Duve (2 October 1917 – 4 May 2013) was a Nobel Prize-winning Belgian cytologist and biochemist. He made serendipitous discoveries of two cell organelles, peroxisome and lysosome, for which he shared ...
, who eventually received the
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
in 1974.
Lysosomes are known to contain more than 60 different enzymes, and have more than 50 membrane proteins. Enzymes of the lysosomes are synthesized in the
rough endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
and exported to the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
upon recruitment by a complex composed of
CLN6
Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the ''CLN6'' gene.
The CLN6 protein is part of the EGRESS complex (ER-to-Golgi relaying of enzymes of the lysosomal system), which recruits lysosomal enzymes at t ...
and
CLN8
Protein CLN8 is a protein that in humans is encoded by the ''CLN8'' gene.
Molecular biology
This gene encodes a transmembrane protein that localizes to the endoplasmic reticulum (ER) and recycles between the ER and the Golgi apparatus via COPII- ...
proteins.
The enzymes are trafficked from the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
to lysosomes in small vesicles, which fuse with larger acidic vesicles. Enzymes destined for a lysosome are specifically tagged with the molecule
mannose 6-phosphate
Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase.
M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transp ...
, so that they are properly sorted into acidified vesicles.
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
Transcription factor EB is a protein that in humans is encoded by the ''TFEB'' gene.
Function
TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane prote ...
), which promotes the transcription of
nuclear gene
A nuclear gene is a gene whose physical DNA nucleotide sequence is located in the cell nucleus of a eukaryote. The term is used to distinguish nuclear genes from genes found in mitochondria or chloroplasts. The vast majority of genes in eukary ...
s.
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in the genes for these enzymes are responsible for more than 50 different human
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s, which are collectively known as
lysosomal storage disease
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
s. 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
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
, cancers,
cardiovascular diseases
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
, and
aging-related diseases.
Etymology and pronunciation
The word ''lysosome'' (, ) is
New Latin
New Latin (also called Neo-Latin or Modern Latin) is the revival of Literary Latin used in original, scholarly, and scientific works since about 1500. Modern scholarly and technical nomenclature, such as in zoological and botanical taxonomy ...
that uses the
combining forms ''lyso-'' (referring to
lysis
Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...
and derived from the Latin ''
lysis
Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...
'', meaning "to loosen", via Ancient Greek λύσις
úsis, and ''
-some'', from ''
soma
Soma may refer to:
Businesses and brands
* SOMA (architects), a New York–based firm of architects
* Soma (company), a company that designs eco-friendly water filtration systems
* SOMA Fabrications, a builder of bicycle frames and other bicycle ...
'', "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
A typographical error (often shortened to typo), also called a misprint, is a mistake (such as a spelling mistake) made in the typing of printed (or electronic) material. Historically, this referred to mistakes in manual type-setting (typography). ...
, which has no doubt been true as often as not.
Discovery
![The Biological bulletin (19756543133)](https://upload.wikimedia.org/wikipedia/commons/4/44/The_Biological_bulletin_%2819756543133%29.jpg)
In 1955 , discovered by “
Christian de Duve
Christian René Marie Joseph, Viscount de Duve (2 October 1917 – 4 May 2013) was a Nobel Prize-winning Belgian cytologist and biochemist. He made serendipitous discoveries of two cell organelles, peroxisome and lysosome, for which he shared ...
,” the chairman of the Laboratory of Physiological Chemistry at the
Catholic University of Louvain
The Catholic Church, also known as the Roman Catholic Church, is the largest Christian church, with 1.3 billion baptized Catholics worldwide . It is among the world's oldest and largest international institutions, and has played a ...
in Belgium, had been studying the mechanism of action of a
pancreatic hormone
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
in liver cells. By 1949, he and his team had focused on the enzyme called
glucose 6-phosphatase
The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:
: D-glucose 6-phos ...
, 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
Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
. 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
In cell biology, cell fractionation is the process used to separate cellular components while preserving individual functions of each component. This is a method that was originally used to demonstrate the cellular location of various biochemical ...
, by which cellular components are separated based on their sizes using
centrifugation
Centrifugation is a mechanical process which involves the use of the centrifugal force to separate particles from a solution according to their size, shape, density, medium viscosity and rotor speed. The denser components of the mixture migrate ...
.
They succeeded in detecting the enzyme activity from the
microsomal
In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, liv ...
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."
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. The same year,
Alex B. Novikoff
Alex Benjamin Novikoff ( ) was a Russian Empire-born American biologist who is recognized for his pioneering works in the discoveries of cell organelles. A victim of American Cold War antagonism to communism that he supported, he is also reco ...
from the
University of Vermont
The University of Vermont (UVM), officially the University of Vermont and State Agricultural College, is a Public university, public Land-grant university, land-grant research university in Burlington, Vermont. It was founded in 1791 and is amon ...
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
Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are este ...
of lysosomes using
light
Light or visible light is electromagnetic radiation that can be perceived by the human eye. Visible light is usually defined as having wavelengths in the range of 400–700 nanometres (nm), corresponding to frequencies of 750–420 tera ...
and electron microscopic studies. de Duve won the
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. However, it has since been concluded that they only play a minor role in
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
.
Function and structure
Lysosomes contain a variety of enzymes, enabling the cell to break down various biomolecules it engulfs, including
peptides
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
,
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s,
carbohydrate
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
s, and
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
s (
lysosomal lipase
Lysosomal lipase is a form of lipase which functions intracellularly, in the lysosomes. Biochemical Significance
The primary function of lysosomal lipase is to hydrolyze lipids such as triglycerides and cholesterol. These fats are transported an ...
). 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
phagosome
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).
A phagosome is formed by the fusion of the cell mem ...
s, they are able to conduct
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
, clearing out damaged structures. Similarly, they are able to break down virus particles or bacteria in
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
of
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s.
The size of lysosomes varies from 0.1
μm to 1.2
μm. With a
pH ranging from ~4.5–5.0, the interior of the lysosomes is acidic compared to the slightly basic
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
(pH 7.2). The lysosomal membrane protects the cytosol, and therefore the rest of the
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
, from the
degradative enzyme A degradative enzyme is an enzyme (in a broader sense a protein) which degrades biological molecules. Some examples of degradative enzymes:
*Lipase, which digests lipids,
*Carbohydrases, which digest carbohydrates (e.g., sugars),
*Proteases, which d ...
s within the lysosome. The cell is additionally protected from any lysosomal acid
hydrolases
Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are este ...
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
proton
A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
s (H
+ ions) from the cytosol across the
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
via
proton pump
A proton pump is an integral membrane protein pump that builds up a proton gradient across a biological membrane
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell f ...
s 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.
It sources its versatile capacity for degradation by import of enzymes with specificity for different substrates;
cathepsin
Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are di ...
s are the major class of hydrolytic enzymes, while
lysosomal alpha-glucosidase is responsible for carbohydrates, and
lysosomal acid phosphatase
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
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
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
(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
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
.
The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes are transcribed in the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
in a process that is controlled by transcription factor EB (
TFEB
Transcription factor EB is a protein that in humans is encoded by the ''TFEB'' gene.
Function
TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane prote ...
).
mRNA transcripts exit the nucleus into the cytosol, where they are translated by
ribosomes
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to f ...
. The nascent peptide chains are
translocated into the rough
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
, where they are modified. Lysosomal soluble proteins exit the endoplasmic reticulum via
COPII
The Coat Protein Complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. This ...
-coated vesicles after recruitment by the
EGRESS complex (ER-to-Golgi relaying of enzymes of the lysosomal system), which is composed of
CLN6
Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the ''CLN6'' gene.
The CLN6 protein is part of the EGRESS complex (ER-to-Golgi relaying of enzymes of the lysosomal system), which recruits lysosomal enzymes at t ...
and
CLN8
Protein CLN8 is a protein that in humans is encoded by the ''CLN8'' gene.
Molecular biology
This gene encodes a transmembrane protein that localizes to the endoplasmic reticulum (ER) and recycles between the ER and the Golgi apparatus via COPII- ...
proteins.
COPII vesicles then deliver lysosomal enzymes to the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
, where a specific lysosomal tag,
mannose 6-phosphate
Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase.
M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transp ...
, is added to the peptides. The presence of these tags allow for binding to
mannose 6-phosphate receptor
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver th ...
s in the Golgi apparatus, a phenomenon that is crucial for proper packaging into vesicles destined for the lysosomal system.
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.
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.
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 cellular biology, pinocytosis, otherwise known as fluid endocytosis and bulk-phase pinocytosis, is a mode of endocytosis in which small molecules dissolved in extracellular fluid are brought into the cell through an invagination of the cell me ...
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.
In addition,
AB5 toxins such as
cholera
Cholera is an infection of the small intestine by some strains of the bacterium ''Vibrio cholerae''. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and ...
hijack the endosomal pathway while evading lysosomal degradation.
Clinical significance
Lysosomes are involved in a group of genetically inherited deficiencies, or mutations called
lysosomal storage diseases
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
(LSD),
inborn errors of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
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
An acid hydrolase is an enzyme that works best at acidic pHs. It is commonly located in lysosomes, which are acidic on the inside. Acid hydrolases may be nucleases, proteases, glycosidases, lipases, phosphatases, sulfatases and phospholipases ...
. 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.
[ This results in abnormal signaling pathways, ]calcium homeostasis
Calcium metabolism is the movement and regulation of calcium ions (Ca2+) ''in'' (via the gut) and ''out'' (via the gut and kidneys) of the body, and ''between'' body compartments: the blood plasma, the extracellular and intracellular fluids, and ...
, lipid biosynthesis and degradation and intracellular trafficking, ultimately leading to pathogenetic disorders. The organs most affected are brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
, viscera
In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a ...
, bone and cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
.
There is no direct medical treatment to cure LSDs. The most common LSD is Gaucher's disease
Gaucher's disease or Gaucher disease () (GD) is a genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polyg ...
, which is due to deficiency of the enzyme glucocerebrosidase
β-Glucocerebrosidase (also called acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase) is an enzyme with glucosylceramidase activity () that is needed to cleave, by hydrolysis, the beta-glycosidic linkage of the chemical g ...
. Consequently, the enzyme substrate, the fatty acid glucosylceramide
Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose.
Clinical significance
In Gaucher disease, the enzyme glucocerebrosidase is nonfunctional and cannot break down glucoc ...
accumulates, particularly in white blood cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, which in turn affects spleen, liver, kidneys, lungs, brain and bone marrow. The disease is characterized by bruises, fatigue, anaemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
, low blood platelets, osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
, and enlargement of the liver and spleen. As of 2017, enzyme replacement therapy
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is availab ...
is available for treating 8 of the 50-60 known LDs.
The most severe and rarely found, lysosomal storage disease is inclusion cell disease.
Metachromatic leukodystrophy
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth ...
is another lysosomal storage disease that also affects sphingolipid metabolism
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...
.
Dysfunctional lysosome activity is also heavily implicated in the biology of aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
, and age-related diseases such as Alzheimer's, Parkinson's, and cardiovascular disease.
Different enzymes present in Lysosomes
Lysosomotropism
Weak bases with lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
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, "acid trapping" or "proton pump" effect. The amount of accumulation of lysosomotropic compounds 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-lives; these properties have been found for drugs such as haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...
, levomepromazine
Levomepromazine, also known as methotrimeprazine, is a phenothiazine neuroleptic drug. Brand names include Nozinan, Levoprome, Detenler, Hirnamin, Levotomin and Neurocil. It is a low-potency antipsychotic (approximately half as potent as chlorpro ...
, and amantadine
Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...
. 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. Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase) and include for example fluoxetine
Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
, sertraline
Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differe ...
, or amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
.
Ambroxol
Ambroxol is a drug that breaks up phlegm, used in the treatment of respiratory diseases associated with viscid or excessive mucus. Ambroxol is often administered as an active ingredient in cough syrup.
It was patented in 1966 and came into med ...
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
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
from acidic calcium stores. Presumably for this reason, Ambroxol
Ambroxol is a drug that breaks up phlegm, used in the treatment of respiratory diseases associated with viscid or excessive mucus. Ambroxol is often administered as an active ingredient in cough syrup.
It was patented in 1966 and came into med ...
was also found to improve cellular function in some disease of lysosomal origin such as Parkinson's or lysosomal storage disease
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
.
Systemic lupus erythematosus
Impaired lysosome function is prominent in systemic lupus erythematosus preventing macrophages and monocytes from degrading neutrophil extracellular traps and immune complexes. The failure to degrade internalized immune complexes stems from chronic mTORC2 activity, which impairs lysosome acidification. As a result, immune complexes in the lysosome recycle to the surface of macrophages causing an accumulation of nuclear antigens upstream of multiple lupus-associated pathologies.
Controversy in botany
By scientific convention, the term lysosome is applied to these vesicular organelles only in animals, and the term vacuole
A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...
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. Some vacuoles contain their own hydrolytic enzymes and perform the classic lysosomal activity, which is autophagy. 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. 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. Vacuoles do not have catabolic activity and do not undergo exocytosis
Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
as lysosomes do.
See also
* Peroxisome
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
* Cathelicidin
Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs); in humans, the ''CAMP'' gene encodes the peptide precursor CAP-18 (18 kDa), which is proce ...
* Antimicrobial peptides
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
* Innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
* TMEM106B Transmembrane protein 106B is a protein that is encoded by the ''TMEM106B'' gene. It is found primarily within Neuron, neurons and Oligodendrocyte, oligodendrocytes in the central nervous system with its subcellular location being in Lysosome, lysos ...
References
External links
*
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 NCATS/Rare Diseases Clinical Research Network
* ttp://content.nejm.org/cgi/content/full/NEJMoa0902630 Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
Animation showing how lysosomes are made, and their function
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Cell anatomy
Organelles
Lysosomal storage diseases