Reactive oxygen species
Encyclopedia
Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen
ion
s and peroxide
s. Reactive oxygen species are highly reactive due to the presence of unpaired valence
shell electrons.
ROS form as a natural byproduct of the normal metabolism of oxygen
and have important roles in cell signaling
and homeostasis
. However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. This cumulates into a situation known as oxidative stress
. ROS are also generated by exogenous sources such as ionizing radiation
.
s, catalase
s, lactoperoxidase
s, glutathione peroxidase
s and peroxiredoxin
s. Small molecule antioxidants such as ascorbic acid
(vitamin C), tocopherol
(vitamin E), uric acid
, and glutathione
also play important roles as cellular antioxidants. In similar manner, polyphenol antioxidant
s assist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is less - e.g., it seems that the most important plasma antioxidant in humans is uric acid
.
Effects of ROS on cell metabolism have been well documented in a variety of species. These include not only roles in apoptosis
(programmed cell death) but also positive effects such as the induction of host defencegenes
and mobilisation of ion transport systems. This implicates them in redox signaling
, also known as oxidative signaling
. In particular, platelets involved in wound
repair and blood
homeostasis
release ROS to recruit additional platelets to sites of injury
. These also provide a link to the adaptive immune system
via the recruitment of leukocytes.
Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including cardiovascular disease
. They may also be involved in hearing impairment
via cochlea
r damage induced by elevated sound levels
, in ototoxicity of drugs such as cisplatin
, and in congenital deafness in both animals and humans. Redox signaling
is also implicated in mediation of apoptosis
or programmed cell death and ischaemic injury. Specific examples include stroke
and heart attack
.
In general, harmful effects of reactive oxygen species on the cell are most often:
s the energy needed to fuel biological functions is produced in the mitochondria via the electron transport chain
. In addition to energy, reactive oxygen species (ROS) that have the potential to cause cellular
damage are produced. ROS can damage DNA
, RNA
, and proteins, which, in theory, contributes to the physiology
of ageing
.
ROS are produced as a normal product of cellular metabolism. In particular, one major contributor to oxidative damage is hydrogen peroxide
(H2O2), which is converted from superoxide
that leaks from the mitochondria. Catalase
and superoxide dismutase
ameliorate the damaging effects of hydrogen peroxide and superoxide by converting these compounds into oxygen
and water
, benign
molecule
s. However, this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects.
Memory capabilities decline with age, evident in human degenerative diseases such as Alzheimer’s disease, which is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism’s fitness
because oxidative damage is a contributor to senescence. In particular, the accumulation of oxidative damage may lead to cognitive dysfunction, as demonstrated in a study in which old rats were given mitochondrial metabolites and then given cognitive tests. Results showed that the rat
s performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function. Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production.
The accumulation of oxidative damage and its implications for aging depends on the particular tissue
type where the damage is occurring. Additional experimental results suggest that oxidative damage is responsible for age-related decline in brain
functioning. Older gerbils were found to have higher levels of oxidized protein in comparison to younger gerbils. Treatment of old and young mice
with a spin trapping compound caused a decrease in the level of oxidized proteins in older gerbils but did not have an effect on younger gerbils. In addition, older gerbils performed cognitive tasks better during treatment but ceased functional capacity when treatment was discontinued, causing oxidized protein levels to increase. This led researchers to conclude that oxidation of cellular proteins is potentially important for brain function (Carney, 1991).
s, such as the mitochondrion
, and also released toward the cytosol. Mitochondria convert energy for the cell into a usable form, adenosine triphosphate
(ATP). The process in which ATP is produced, called oxidative phosphorylation
, involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane by means of the electron transport chain
. In the electron transport chain, electrons are passed through a series of protein
s via oxidation-reduction reactions, with each acceptor protein along the chain having a greater reduction potential than the previous. The last destination for an electron along this chain is an oxygen molecule. In normal conditions, the oxygen is reduced to produce water; however, in about 0.1–2% of electrons passing through the chain (this number derives from studies in isolated mitochondria, though the exact rate in live organisms is yet to be fully agreed upon), oxygen is instead prematurely and incompletely reduced to give the superoxide radical (·O2-), most well documented for Complex I and Complex III. Superoxide is not particularly reactive by itself, but can inactivate specific enzymes or initiate lipid peroxidation
in its protonated form, hydroperoxyl HO2
·. The pKa of hydroperoxyl is 4.8. Thus, at physiological pH, the majority will exist as superoxide.
If too much damage is caused to its mitochondria, a cell undergoes apoptosis
or programmed cell death. Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out. This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell’s cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes. The apoptosome
s bind to and activate caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.
, oxidative damage initiated by reactive oxygen species is a major contributor to the functional decline that is characteristic of aging. While studies in invertebrate models indicate that animals genetically engineered to lack specific antioxidant enzymes (such as SOD), in general, show a shortened lifespan (as one would expect from the theory), the converse manipulation, increasing the levels of antioxidant enzymes, has yielded inconsistent effects on lifespan (though some well-performed studies in Drosophila
do show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes).
Egg Oil
, which contains natural Omega-3 and Omega-6 fatty acids, reduces the effects of aging by absorbing the reactive oxygen species.
In mice, the story is somewhat similar. Deleting antioxidant enzymes, in general, yields shorter lifespan, though overexpression studies have not (with some recent exceptions) consistently extended lifespan.
s (SOD) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. In mammals and most chordates, three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria and SOD3 is extracellular. The first is a dimer (consists of two units), while the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, while SOD2 has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
The SOD-catalysed dismutation of superoxide
may be written with the following half-reactions :
where M = Cu
(n=1) ; Mn
(n=2) ; Fe
(n=2) ; Ni
(n=2).
In this reaction the oxidation state
of the metal cation oscillates between n and n+1.
Catalase, which is concentrated in peroxisomes located next to mitochondria, reacts with the hydrogen peroxide to catalyze the formation of water and oxygen. Glutathione peroxidase
reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur-containing protein called glutathione
. The selenium contained in these enzymes acts as the reactive center, carrying reactive electrons from the peroxide to the glutathione. Peroxiredoxins also degrade H2O2, within the mitochondria, cytosol, and nucleus.
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s and peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
s. Reactive oxygen species are highly reactive due to the presence of unpaired valence
Valence (chemistry)
In chemistry, valence, also known as valency or valence number, is a measure of the number of bonds formed by an atom of a given element. "Valence" can be defined as the number of valence bonds...
shell electrons.
ROS form as a natural byproduct of the normal metabolism of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
and have important roles in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
and homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
. However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. This cumulates into a situation known as oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. ROS are also generated by exogenous sources such as ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
.
Damaging effects
Under normal circumstances, cells are able to defend themselves against ROS damage with enzymes such as superoxide dismutaseSuperoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
s, catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
s, lactoperoxidase
Lactoperoxidase
Lactoperoxidase is a peroxidase enzyme secreted from mammary, salivary, and other mucosal glands that functions as a natural antibacterial agent. Lactoperoxidase is a member of the heme peroxidase family of enzymes. In humans, lactoperoxidase is encoded by the LPO gene.Lactoperoxidase catalyzes...
s, glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...
s and peroxiredoxin
Peroxiredoxin
Peroxiredoxins are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells.- Classification :...
s. Small molecule antioxidants such as ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
(vitamin C), tocopherol
Tocopherol
Tocopherols are a class of chemical compounds of which many have vitamin E activity. It is a series of organic compounds consisting of various methylated phenols...
(vitamin E), uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
, and glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
also play important roles as cellular antioxidants. In similar manner, polyphenol antioxidant
Polyphenol antioxidant
A polyphenol antioxidant is a type of antioxidant containing a polyphenolic substructure. Numbering over 4,000 distinct species, many of these compounds have antioxidant activity in vitro but are unlikely to have antioxidant roles in vivo...
s assist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is less - e.g., it seems that the most important plasma antioxidant in humans is uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
.
Effects of ROS on cell metabolism have been well documented in a variety of species. These include not only roles in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(programmed cell death) but also positive effects such as the induction of host defencegenes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
and mobilisation of ion transport systems. This implicates them in redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
, also known as oxidative signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
. In particular, platelets involved in wound
Wound
A wound is a type of injury in which skin is torn, cut or punctured , or where blunt force trauma causes a contusion . In pathology, it specifically refers to a sharp injury which damages the dermis of the skin.-Open:...
repair and blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
release ROS to recruit additional platelets to sites of injury
Injury
-By cause:*Traumatic injury, a body wound or shock produced by sudden physical injury, as from violence or accident*Other injuries from external physical causes, such as radiation injury, burn injury or frostbite*Injury from infection...
. These also provide a link to the adaptive immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
via the recruitment of leukocytes.
Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. They may also be involved in hearing impairment
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
via cochlea
Cochlea
The cochlea is the auditory portion of the inner ear. It is a spiral-shaped cavity in the bony labyrinth, making 2.5 turns around its axis, the modiolus....
r damage induced by elevated sound levels
Noise health effects
Noise health effects are the health consequences of elevated sound levels. Elevated workplace or other noise can cause hearing impairment, hypertension, ischemic heart disease, annoyance and sleep disturbance. Changes in the immune system and birth defects have been attributed to noise exposure...
, in ototoxicity of drugs such as cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, and in congenital deafness in both animals and humans. Redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
is also implicated in mediation of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
or programmed cell death and ischaemic injury. Specific examples include stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
.
In general, harmful effects of reactive oxygen species on the cell are most often:
- damage of DNA
- oxidations of polyunsaturated fatty acids in lipids (lipid peroxidationLipid peroxidationLipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
) - oxidations of amino acids in proteins
- oxidatively inactivate specific enzymes by oxidation of co-factors
Pathogen Response
When a plant recognizes an attacking pathogen one of the first induced reactions is to rapidly produce superoxide or hydrogen peroxide to strengthen the cell wall. This prevents the spread of the pathogen to other parts of the plant, essentially forming a net around the pathogen to restrict movement and reproduction.Oxidative damage
In aerobic organismAerobic organism
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...
s the energy needed to fuel biological functions is produced in the mitochondria via the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. In addition to energy, reactive oxygen species (ROS) that have the potential to cause cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
damage are produced. ROS can damage DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, and proteins, which, in theory, contributes to the physiology
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
of ageing
Ageing
Ageing or aging is the accumulation of changes in a person over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...
.
ROS are produced as a normal product of cellular metabolism. In particular, one major contributor to oxidative damage is hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
(H2O2), which is converted from superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
that leaks from the mitochondria. Catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
and superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
ameliorate the damaging effects of hydrogen peroxide and superoxide by converting these compounds into oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s. However, this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects.
Memory capabilities decline with age, evident in human degenerative diseases such as Alzheimer’s disease, which is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism’s fitness
Physical fitness
Physical fitness comprises two related concepts: general fitness , and specific fitness...
because oxidative damage is a contributor to senescence. In particular, the accumulation of oxidative damage may lead to cognitive dysfunction, as demonstrated in a study in which old rats were given mitochondrial metabolites and then given cognitive tests. Results showed that the rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function. Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production.
The accumulation of oxidative damage and its implications for aging depends on the particular tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
type where the damage is occurring. Additional experimental results suggest that oxidative damage is responsible for age-related decline in brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
functioning. Older gerbils were found to have higher levels of oxidized protein in comparison to younger gerbils. Treatment of old and young mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
with a spin trapping compound caused a decrease in the level of oxidized proteins in older gerbils but did not have an effect on younger gerbils. In addition, older gerbils performed cognitive tasks better during treatment but ceased functional capacity when treatment was discontinued, causing oxidized protein levels to increase. This led researchers to conclude that oxidation of cellular proteins is potentially important for brain function (Carney, 1991).
Internal production
Free radicals are mainly produced inside organelleOrganelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s, such as the mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
, and also released toward the cytosol. Mitochondria convert energy for the cell into a usable form, adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP). The process in which ATP is produced, called oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane by means of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. In the electron transport chain, electrons are passed through a series of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s via oxidation-reduction reactions, with each acceptor protein along the chain having a greater reduction potential than the previous. The last destination for an electron along this chain is an oxygen molecule. In normal conditions, the oxygen is reduced to produce water; however, in about 0.1–2% of electrons passing through the chain (this number derives from studies in isolated mitochondria, though the exact rate in live organisms is yet to be fully agreed upon), oxygen is instead prematurely and incompletely reduced to give the superoxide radical (·O2-), most well documented for Complex I and Complex III. Superoxide is not particularly reactive by itself, but can inactivate specific enzymes or initiate lipid peroxidation
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
in its protonated form, hydroperoxyl HO2
Hydroperoxyl
The hydroperoxyl radical, also known as the perhydroxyl radical, is the protonated form of superoxide with the chemical formula HO2.-Reactivity:The superoxide anion, O2−, and the hydroperoxyl radical are in equilibrium in aqueous solution:...
·. The pKa of hydroperoxyl is 4.8. Thus, at physiological pH, the majority will exist as superoxide.
If too much damage is caused to its mitochondria, a cell undergoes apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
or programmed cell death. Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out. This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell’s cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes. The apoptosome
Apoptosome
The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...
s bind to and activate caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.
Cause of aging
According to the Free-radical theoryFree-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
, oxidative damage initiated by reactive oxygen species is a major contributor to the functional decline that is characteristic of aging. While studies in invertebrate models indicate that animals genetically engineered to lack specific antioxidant enzymes (such as SOD), in general, show a shortened lifespan (as one would expect from the theory), the converse manipulation, increasing the levels of antioxidant enzymes, has yielded inconsistent effects on lifespan (though some well-performed studies in Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
do show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes).
Egg Oil
Egg Oil
Egg Oil , also known as egg yolk oil , is derived from the yolk of chicken eggs consisting mainly of triglycerides with traces of lecithin and is usually free of egg proteins...
, which contains natural Omega-3 and Omega-6 fatty acids, reduces the effects of aging by absorbing the reactive oxygen species.
In mice, the story is somewhat similar. Deleting antioxidant enzymes, in general, yields shorter lifespan, though overexpression studies have not (with some recent exceptions) consistently extended lifespan.
Superoxide dismutase
Superoxide dismutaseSuperoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
s (SOD) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. In mammals and most chordates, three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria and SOD3 is extracellular. The first is a dimer (consists of two units), while the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, while SOD2 has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
The SOD-catalysed dismutation of superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
may be written with the following half-reactions :
- M(n+1)+ − SOD + O2− → Mn+ − SOD + O2
- Mn+ − SOD + O2− + 2H+ → M(n+1)+ − SOD + H2O2.
where M = Cu
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
(n=1) ; Mn
Manganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
(n=2) ; Fe
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
(n=2) ; Ni
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
(n=2).
In this reaction the oxidation state
Oxidation state
In chemistry, the oxidation state is an indicator of the degree of oxidation of an atom in a chemical compound. The formal oxidation state is the hypothetical charge that an atom would have if all bonds to atoms of different elements were 100% ionic. Oxidation states are typically represented by...
of the metal cation oscillates between n and n+1.
Catalase, which is concentrated in peroxisomes located next to mitochondria, reacts with the hydrogen peroxide to catalyze the formation of water and oxygen. Glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...
reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur-containing protein called glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
. The selenium contained in these enzymes acts as the reactive center, carrying reactive electrons from the peroxide to the glutathione. Peroxiredoxins also degrade H2O2, within the mitochondria, cytosol, and nucleus.
- 2 H2O2 → 2 H2O + O2 (catalase)
- 2GSH + H2O2 → GS–SG + 2H2O (glutathione peroxidase)
ROS-directed cancer chemotherapeutics
Recent research demonstrates that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through ROS represents a specific vulnerability of malignant cells that can be selectively targeted by pro- and antioxidant redox chemotherapeutics.See also
- AntioxidantAntioxidantAn antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
- MelaninMelaninMelanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
- Mitohormesis
- Oxidative stressOxidative stressOxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
- Oxygen toxicityOxygen toxicityOxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at elevated partial pressures. It is also known as oxygen toxicity syndrome, oxygen intoxication, and oxygen poisoning...
- Polyphenol antioxidantPolyphenol antioxidantA polyphenol antioxidant is a type of antioxidant containing a polyphenolic substructure. Numbering over 4,000 distinct species, many of these compounds have antioxidant activity in vitro but are unlikely to have antioxidant roles in vivo...
s - Pro-oxidantPro-oxidantPro-oxidants are chemicals that induce oxidative stress, through either creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues...
- Redox signalingRedox signalingRedox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
- IodideIodideAn iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. This page is for the iodide ion and its salts. For information on organoiodides, see organohalides. In everyday life, iodide is most commonly encountered as a component of iodized salt,...