Oxidative Phosphorylation
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Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...
in which cells use
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s to
oxidize Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
nutrient A nutrient is a substance used by an organism to survive, grow and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s, thereby releasing chemical energy in order to produce
adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...
(ATP). In
eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...
, this takes place inside
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
. Almost all
aerobic organism An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment. The ability to exhibit aerobic respiration may yield benefits to the aerobic organism, as aerobic respiration yields more energy than anaerobic ...
s carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative
fermentation Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
processes such as anaerobic glycolysis. The energy stored in the chemical bonds of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
is released by the cell in the
citric acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
, producing carbon dioxide and the energetic electron donors
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
and FADH. Oxidative phosphorylation uses these molecules and O2 to produce ATP, which is used throughout the cell whenever energy is needed. During oxidative phosphorylation, electrons are transferred from the electron donors to a series of electron acceptors in a series of
redox reaction Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
s ending in oxygen, whose reaction releases half of the total energy.Voet, D.; Voet, J. G. (2004). "Biochemistry", 3rd ed., p. 804, Wiley.ISBN 0-471-19350-X. In
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s, these redox reactions are catalyzed by a series of
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain. ...
es within the inner membrane of the cell's mitochondria, whereas, in
prokaryote A prokaryote (; less commonly spelled procaryote) is a unicellular organism, single-celled organism whose cell (biology), cell lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Gree ...
s, these proteins are located in the cell's outer membrane. These linked sets of proteins are called the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
. In eukaryotes, five main protein complexes are involved, whereas in prokaryotes many different enzymes are present, using a variety of electron donors and acceptors. The energy transferred by electrons flowing through this electron transport chain is used to transport
proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...
s across the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
, in a process called '' electron transport''. This generates
potential energy In physics, potential energy is the energy of an object or system due to the body's position relative to other objects, or the configuration of its particles. The energy is equal to the work done against any restoring forces, such as gravity ...
in the form of a pH gradient and the resulting
electrical potential Electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as electric potential energy per unit of electric charge. More precisely, electric potential is the amount of work neede ...
across this membrane. This store of energy is tapped when protons flow back across the membrane and down the potential energy gradient, through a large enzyme called ATP synthase in a process called
chemiosmosis Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ion ...
. The ATP synthase uses the energy to transform
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
(ADP) into adenosine triphosphate, in a
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
reaction. The reaction is driven by the proton flow, which forces the
rotation Rotation or rotational/rotary motion is the circular movement of an object around a central line, known as an ''axis of rotation''. A plane figure can rotate in either a clockwise or counterclockwise sense around a perpendicular axis intersect ...
of a part of the enzyme. The ATP synthase is a rotary mechanical motor. Although oxidative phosphorylation is a vital part of metabolism, it produces
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
such as
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
and
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
, which lead to propagation of
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired electron, unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemical reaction, chemi ...
, damaging cells and contributing to
disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
and, possibly,
aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
and
senescence Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...
. The enzymes carrying out this metabolic pathway are also the target of many drugs and poisons that inhibit their activities.


Chemiosmosis

Oxidative phosphorylation works by using
energy Energy () is the physical quantity, quantitative physical property, property that is transferred to a physical body, body or to a physical system, recognizable in the performance of Work (thermodynamics), work and in the form of heat and l ...
-releasing chemical reactions to drive energy-requiring reactions. The two sets of reactions are said to be ''coupled''. This means one cannot occur without the other. The chain of redox reactions driving the flow of electrons through the electron transport chain, from electron donors such as
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
to
electron acceptor An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. Electron acceptors are oxidizing agents. The electron accepting power of an electron acceptor is measured by its redox potential. In the ...
s such as
oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
and hydrogen (protons), is an exergonic process – it releases energy, whereas the synthesis of ATP is an endergonic process, which requires an input of energy. Both the electron transport chain and the ATP synthase are embedded in a membrane, and energy is transferred from the electron transport chain to the ATP synthase by movements of protons across this membrane, in a process called ''
chemiosmosis Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ion ...
''. A current of protons is driven from the negative N-side of the membrane to the positive P-side through the proton-pumping enzymes of the electron transport chain. The movement of protons creates an
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts: * The chemical gradient, or difference in Concentration, solute concentration across ...
across the membrane, is called the
proton-motive force Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate (ATP) by the movement of hydrogen ions (H+) across a membra ...
. It has two components: a difference in proton concentration (a H+ gradient, Δ pH) and a difference in
electric potential Electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as electric potential energy per unit of electric charge. More precisely, electric potential is the amount of work (physic ...
, with the N-side having a negative charge. ATP synthase releases this stored energy by completing the circuit and allowing protons to flow down the electrochemical gradient, back to the N-side of the membrane. The electrochemical gradient drives the rotation of part of the enzyme's structure and couples this motion to the synthesis of ATP. The two components of the proton-motive force are
thermodynamic Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by the four laws of th ...
ally equivalent: In mitochondria, the largest part of energy is provided by the potential; in alkaliphile bacteria the electrical energy even has to compensate for a counteracting inverse pH difference. Inversely,
chloroplast A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...
s operate mainly on ΔpH. However, they also require a small membrane potential for the kinetics of ATP synthesis. In the case of the
fusobacterium ''Fusobacterium'' is a genus of obligate anaerobic, Gram-negative, non-sporeforming bacteria belonging to Gracilicutes. Individual cells are slender, rod-shaped bacilli with pointed ends. ''Fusobacterium'' was discovered in 1900 by Courmont an ...
'' Propionigenium modestum'' it drives the counter-rotation of subunits a and c of the FO motor of ATP synthase. The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by anaerobic fermentation.
Glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one molecule of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
to carbon dioxide and water, while each cycle of
beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...
of a
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
yields about 14 ATPs. These ATP yields are theoretical maximum values; in practice, some protons leak across the membrane, lowering the yield of ATP.


Electron and proton transfer molecules

The electron transport chain carries both protons and electrons, passing electrons from donors to acceptors, and transporting protons across a membrane. These processes use both soluble and protein-bound transfer molecules. In the mitochondria, electrons are transferred within the intermembrane space by the water-
soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
electron transfer protein cytochrome c. This carries only electrons, and these are transferred by the reduction and oxidation of an
iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
atom that the protein holds within a
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
group in its structure. Cytochrome c is also found in some bacteria, where it is located within the periplasmic space. Within the inner mitochondrial membrane, the
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
-soluble electron carrier
coenzyme Q10 Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, seed oils, vegetables, ...
(Q) carries both electrons and protons by a
redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...
cycle. This small benzoquinone molecule is very
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
, so it diffuses freely within the membrane. When Q accepts two electrons and two protons, it becomes reduced to the ''
ubiquinol A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans. The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
'' form (QH2); when QH2 releases two electrons and two protons, it becomes oxidized back to the ''ubiquinone'' (Q) form. As a result, if two enzymes are arranged so that Q is reduced on one side of the membrane and QH2 oxidized on the other, ubiquinone will couple these reactions and shuttle protons across the membrane. Some bacterial electron transport chains use different quinones, such as
menaquinone Vitamin K2 or menaquinone (MK) () is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in an ...
, in addition to ubiquinone. Within proteins, electrons are transferred between flavin cofactors, iron–sulfur clusters and cytochromes. There are several types of iron–sulfur cluster. The simplest kind found in the electron transfer chain consists of two iron atoms joined by two atoms of inorganic
sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...
; these are called Fe–2Sclusters. The second kind, called Fe–4S contains a cube of four iron atoms and four sulfur atoms. Each iron atom in these clusters is coordinated by an additional
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
, usually by the sulfur atom of
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
. Metal ion cofactors undergo redox reactions without binding or releasing protons, so in the electron transport chain they serve solely to transport electrons through proteins. Electrons move quite long distances through proteins by hopping along chains of these cofactors. This occurs by
quantum tunnelling In physics, quantum tunnelling, barrier penetration, or simply tunnelling is a quantum mechanical phenomenon in which an object such as an electron or atom passes through a potential energy barrier that, according to classical mechanics, shoul ...
, which is rapid over distances of less than 1.4 m.


Eukaryotic electron transport chains

Many
catabolic Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipi ...
biochemical processes, such as
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
, the
citric acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
, and
beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...
, produce the reduced
coenzyme A cofactor is a non-protein chemical compound or Metal ions in aqueous solution, metallic ion that is required for an enzyme's role as a catalysis, catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can ...
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
. This coenzyme contains electrons that have a high transfer potential; in other words, they will release a large amount of energy upon oxidation. However, the cell does not release this energy all at once, as this would be an uncontrollable reaction. Instead, the electrons are removed from NADH and passed to oxygen through a series of enzymes that each release a small amount of the energy. This set of enzymes, consisting of complexes I through IV, is called the electron transport chain and is found in the
inner membrane of the mitochondrion The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
.
Succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into Fuma ...
is also oxidized by the electron transport chain, but feeds into the pathway at a different point. In
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s, the enzymes in this electron transport system use the energy released from O2 by NADH to pump
proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...
s across the inner membrane of the mitochondrion. This causes protons to build up in the
intermembrane space The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the Inner mitochondrial membrane, inner membrane and the Outer mitochondrial memb ...
, and generates an
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts: * The chemical gradient, or difference in Concentration, solute concentration across ...
across the membrane. The energy stored in this potential is then used by ATP synthase to produce ATP. Oxidative phosphorylation in the eukaryotic mitochondrion is the best-understood example of this process. The mitochondrion is present in almost all eukaryotes, with the exception of anaerobic protozoa such as ''
Trichomonas vaginalis ''Trichomonas vaginalis'' is an Anaerobic organism, anaerobic, flagellated protozoan parasite and the causative agent of a Sexually transmitted infection, sexually transmitted disease called trichomoniasis. It is the most common pathogenic protoz ...
'' that instead reduce protons to hydrogen in a remnant mitochondrion called a
hydrogenosome A hydrogenosome is a membrane-enclosed organelle found in some Anaerobic organism, anaerobic Ciliate, ciliates, Flagellate, flagellates, Fungus, fungi, and three species of Loricifera, loriciferans. Hydrogenosomes are highly variable organelles t ...
.


NADH-coenzyme Q oxidoreductase (complex I)

NADH-coenzyme Q oxidoreductase, also known as ''NADH dehydrogenase'' or ''complex I'', is the first protein in the electron transport chain. Complex I is a giant
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
with the mammalian complex I having 46 subunits and a molecular mass of about 1,000 kilodaltons (kDa). The structure is known in detail only from a bacterium; in most organisms the complex resembles a boot with a large "ball" poking out from the membrane into the mitochondrion. The genes that encode the individual proteins are contained in both the
cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
and the mitochondrial genome, as is the case for many enzymes present in the mitochondrion. The reaction that is catalyzed by this enzyme is the two electron oxidation of
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
by
coenzyme Q10 Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, seed oils, vegetables, ...
or ''ubiquinone'' (represented as Q in the equation below), a lipid-soluble
quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...
that is found in the mitochondrion membrane: The start of the reaction, and indeed of the entire electron chain, is the binding of a NADH molecule to complex I and the donation of two electrons. The electrons enter complex I via a
prosthetic group A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein. Not to be confused with the cosubstrate that binds to the enzyme apoenzyme (e ...
attached to the complex,
flavin mononucleotide Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...
(FMN). The addition of electrons to FMN converts it to its reduced form, FMNH2. The electrons are then transferred through a series of iron–sulfur clusters: the second kind of prosthetic group present in the complex. There are both Fe–2Sand Fe–4Siron–sulfur clusters in complex I. As the electrons pass through this complex, four protons are pumped from the matrix into the intermembrane space. Exactly how this occurs is unclear, but it seems to involve
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...
s in complex I that cause the protein to bind protons on the N-side of the membrane and release them on the P-side of the membrane. Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane. Reduction of ubiquinone also contributes to the generation of a proton gradient, as two protons are taken up from the matrix as it is reduced to
ubiquinol A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans. The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
(QH2).


Succinate-Q oxidoreductase (complex II)

Succinate-Q oxidoreductase, also known as ''complex II'' or ''succinate dehydrogenase'', is a second entry point to the electron transport chain. It is unusual because it is the only enzyme that is part of both the citric acid cycle and the electron transport chain. Complex II consists of four protein subunits and contains a bound
flavin adenine dinucleotide In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...
(FAD) cofactor, iron–sulfur clusters, and a
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
group that does not participate in electron transfer to coenzyme Q, but is believed to be important in decreasing production of reactive oxygen species. It oxidizes
succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into Fuma ...
to
fumarate Fumaric acid or ''trans''-butenedioic acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The sa ...
and reduces ubiquinone. As this reaction releases less energy than the oxidation of NADH, complex II does not transport protons across the membrane and does not contribute to the proton gradient. In some eukaryotes, such as the
parasitic worm Parasitic worms, also known as helminths, are a polyphyletic group of large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other par ...
''
Ascaris suum ''Ascaris suum'', also known as the large roundworm of pig, is a parasitic nematode that causes ascariasis in pigs. While roundworms in pigs and humans are today considered as two species (''A. suum'' and '' A. lumbricoides'') with different ho ...
'', an enzyme similar to complex II, fumarate reductase (menaquinol:fumarate oxidoreductase, or QFR), operates in reverse to oxidize ubiquinol and reduce fumarate. This allows the worm to survive in the anaerobic environment of the
large intestine The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the Digestion, digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces befor ...
, carrying out anaerobic oxidative phosphorylation with fumarate as the electron acceptor. Another unconventional function of complex II is seen in the
malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
parasite ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''. Here, the reversed action of complex II as an oxidase is important in regenerating ubiquinol, which the parasite uses in an unusual form of
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...
biosynthesis.


Electron transfer flavoprotein-Q oxidoreductase

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-Q oxidoreductase), also known as ''electron transferring-flavoprotein dehydrogenase'', is a third entry point to the electron transport chain. It is an enzyme that accepts electrons from electron-transferring flavoprotein in the mitochondrial matrix, and uses these electrons to reduce ubiquinone. This enzyme contains a flavin and a Fe–4Scluster, but, unlike the other respiratory complexes, it attaches to the surface of the membrane and does not cross the lipid bilayer. In mammals, this metabolic pathway is important in
beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...
of
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
s and catabolism of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s and
choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...
, as it accepts electrons from multiple
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
dehydrogenases. In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.


Q-cytochrome c oxidoreductase (complex III)

Q-cytochrome c oxidoreductase is also known as ''cytochrome c reductase'', ''cytochrome bc1 complex'', or simply ''complex III''. In mammals, this enzyme is a dimer, with each subunit complex containing 11 protein subunits, an Fe-2Siron–sulfur cluster and three
cytochrome Cytochromes are redox-active proteins containing a heme, with a central iron (Fe) atom at its core, as a cofactor. They are involved in the electron transport chain and redox catalysis. They are classified according to the type of heme and its ...
s: one
cytochrome Cytochromes are redox-active proteins containing a heme, with a central iron (Fe) atom at its core, as a cofactor. They are involved in the electron transport chain and redox catalysis. They are classified according to the type of heme and its ...
c1 and two b cytochromes. A cytochrome is a kind of electron-transferring protein that contains at least one
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
group. The iron atoms inside complex III's heme groups alternate between a reduced ferrous (+2) and oxidized ferric (+3) state as the electrons are transferred through the protein. The reaction catalyzed by complex III is the oxidation of one molecule of
ubiquinol A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans. The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
and the reduction of two molecules of cytochrome c, a heme protein loosely associated with the mitochondrion. Unlike coenzyme Q, which carries two electrons, cytochrome c carries only one electron. As only one of the electrons can be transferred from the QH2 donor to a cytochrome c acceptor at a time, the reaction mechanism of complex III is more elaborate than those of the other respiratory complexes, and occurs in two steps called the
Q cycle The Q cycle (named for ''quinol'') describes a series of sequential oxidation and reduction of the lipophilic electron carrier Coenzyme Q (CoQ) between the ubiquinol and ubiquinone forms. These reactions can result in the net movement of proton ...
. In the first step, the enzyme binds three substrates, first, QH2, which is then oxidized, with one electron being passed to the second substrate, cytochrome c. The two protons released from QH2 pass into the intermembrane space. The third substrate is Q, which accepts the second electron from the QH2 and is reduced to Q.−, which is the ubisemiquinone
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...
. The first two substrates are released, but this ubisemiquinone intermediate remains bound. In the second step, a second molecule of QH2 is bound and again passes its first electron to a cytochrome c acceptor. The second electron is passed to the bound ubisemiquinone, reducing it to QH2 as it gains two protons from the mitochondrial matrix. This QH2 is then released from the enzyme. As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, a net transfer of protons across the membrane occurs, adding to the proton gradient. The rather complex two-step mechanism by which this occurs is important, as it increases the efficiency of proton transfer. If, instead of the Q cycle, one molecule of QH2 were used to directly reduce two molecules of cytochrome c, the efficiency would be halved, with only one proton transferred per cytochrome c reduced.


Cytochrome c oxidase (complex IV)

Cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes. It is the last enzyme in the Cellular respir ...
, also known as ''complex IV'', is the final protein complex in the electron transport chain. The mammalian enzyme has an extremely complicated structure and contains 13 subunits, two heme groups, as well as multiple metal ion cofactors – in all, three atoms of
copper Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...
, one of
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
and one of
zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
. This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen and hydrogen (protons), while pumping protons across the membrane. The final
electron acceptor An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. Electron acceptors are oxidizing agents. The electron accepting power of an electron acceptor is measured by its redox potential. In the ...
oxygen is reduced to water in this step. Both the direct pumping of protons and the consumption of matrix protons in the reduction of oxygen contribute to the proton gradient. The reaction catalyzed is the oxidation of cytochrome c and the reduction of oxygen:


Alternative reductases and oxidases

Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes described above. For example,
plant Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...
s have alternative NADH oxidases, which oxidize NADH in the cytosol rather than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool. These enzymes do not transport protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner membrane. Another example of a divergent electron transport chain is the '' alternative oxidase'', which is found in
plant Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...
s, as well as some
fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
,
protist A protist ( ) or protoctist is any eukaryotic organism that is not an animal, land plant, or fungus. Protists do not form a natural group, or clade, but are a paraphyletic grouping of all descendants of the last eukaryotic common ancest ...
s, and possibly some animals. This enzyme transfers electrons directly from ubiquinol to oxygen. The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower ATP yields than the full pathway. The advantages produced by a shortened pathway are not entirely clear. However, the alternative oxidase is produced in response to stresses such as cold,
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
, and infection by pathogens, as well as other factors that inhibit the full electron transport chain. Alternative pathways might, therefore, enhance an organism's resistance to injury, by reducing
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
.


Organization of complexes

The original model for how the respiratory chain complexes are organized was that they diffuse freely and independently in the mitochondrial membrane. However, recent data suggest that the complexes might form higher-order structures called supercomplexes or " respirasomes". In this model, the various complexes exist as organized sets of interacting enzymes. These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer. Within such mammalian supercomplexes, some components would be present in higher amounts than others, with some data suggesting a ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4. However, the debate over this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model.


Prokaryotic electron transport chains

In contrast to the general similarity in structure and function of the electron transport chains in eukaryotes,
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
and
archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
possess a large variety of electron-transfer enzymes. These use an equally wide set of chemicals as substrates. In common with eukaryotes, prokaryotic electron transport uses the energy released from the oxidation of a substrate to pump ions across a membrane and generate an electrochemical gradient. In the bacteria, oxidative phosphorylation in ''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' is understood in most detail, while archaeal systems are at present poorly understood. The main difference between eukaryotic and prokaryotic oxidative phosphorylation is that bacteria and archaea use many different substances to donate or accept electrons. This allows prokaryotes to grow under a wide variety of environmental conditions. In ''E. coli'', for example, oxidative phosphorylation can be driven by a large number of pairs of reducing agents and oxidizing agents, which are listed below. The midpoint potential of a chemical measures how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and oxidizing agents positive potentials. As shown above, ''E. coli'' can grow with reducing agents such as formate, hydrogen, or lactate as electron donors, and nitrate, DMSO, or oxygen as acceptors. The larger the difference in midpoint potential between an oxidizing and reducing agent, the more energy is released when they react. Out of these compounds, the succinate/fumarate pair is unusual, as its midpoint potential is close to zero. Succinate can therefore be oxidized to fumarate if a strong oxidizing agent such as oxygen is available, or fumarate can be reduced to succinate using a strong reducing agent such as formate. These alternative reactions are catalyzed by
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...
and fumarate reductase, respectively. Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, nitrifying bacteria such as '' Nitrobacter'' oxidize nitrite to nitrate, donating the electrons to oxygen. The small amount of energy released in this reaction is enough to pump protons and generate ATP, but not enough to produce NADH or NADPH directly for use in
anabolism Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an Endergonic reaction, endergonic process. Anabolism is the building-up aspect of metabo ...
. This problem is solved by using a nitrite oxidoreductase to produce enough proton-motive force to run part of the electron transport chain in reverse, causing complex I to generate NADH. Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced, in response to environmental conditions. This flexibility is possible because different oxidases and reductases use the same ubiquinone pool. This allows many combinations of enzymes to function together, linked by the common ubiquinol intermediate. These respiratory chains therefore have a
modular design Modular design, or modularity in design, is a design principle that subdivides a system into smaller parts called ''modules'' (such as modular process skids), which can be independently created, modified, replaced, or exchanged with other modules ...
, with easily interchangeable sets of enzyme systems. In addition to this metabolic diversity, prokaryotes also possess a range of
isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...
s – different enzymes that catalyze the same reaction. For example, in ''E. coli'', there are two different types of ubiquinol oxidase using oxygen as an electron acceptor. Under highly aerobic conditions, the cell uses an oxidase with a low affinity for oxygen that can transport two protons per electron. However, if levels of oxygen fall, they switch to an oxidase that transfers only one proton per electron, but has a high affinity for oxygen.


ATP synthase (complex V)

ATP synthase, also called ''complex V'', is the final enzyme in the oxidative phosphorylation pathway. This enzyme is found in all forms of life and functions in the same way in both prokaryotes and eukaryotes. The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and
phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
(Pi). Estimates of the number of protons required to synthesize one ATP have ranged from three to four, with some suggesting cells can vary this ratio, to suit different conditions. This
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
reaction is an
equilibrium Equilibrium may refer to: Film and television * ''Equilibrium'' (film), a 2002 science fiction film * '' The Story of Three Loves'', also known as ''Equilibrium'', a 1953 romantic anthology film * "Equilibrium" (''seaQuest 2032'') * ''Equilibr ...
, which can be shifted by altering the proton-motive force. In the absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their concentration gradient and turning ADP into ATP. Indeed, in the closely related vacuolar type H+-ATPases, the hydrolysis reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP. ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains 16 subunits and has a mass of approximately 600
kilodalton The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
s. The portion embedded within the membrane is called FO and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F1 and is the site of ATP synthesis. The ball-shaped complex at the end of the F1 portion contains six proteins of two different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with the tip of the stalk extending into the ball of α and β subunits. Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F1 portion and back into the membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme. As protons cross the membrane through the channel in the base of ATP synthase, the FO proton-driven motor rotates. Rotation might be caused by changes in the
ionization Ionization or ionisation is the process by which an atom or a molecule acquires a negative or positive Electric charge, charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged at ...
of amino acids in the ring of c subunits causing
electrostatic Electrostatics is a branch of physics that studies slow-moving or stationary electric charges. Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word (), mean ...
interactions that propel the ring of c subunits past the proton channel. This rotating ring in turn drives the rotation of the central
axle An axle or axletree is a central shaft for a rotation, rotating wheel and axle, wheel or gear. On wheeled vehicles, the axle may be fixed to the wheels, rotating with them, or fixed to the vehicle, with the wheels rotating around the axle. In ...
(the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented from rotating themselves by the side-arm, which acts as a
stator The stator is the stationary part of a rotary system, found in electric generators, electric motors, sirens, mud motors, or biological rotors (such as bacterial flagella or ATP synthase). Energy flows through a stator to or from the rotat ...
. This movement of the tip of the γ subunit within the ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements that produces and then releases ATP. This ATP synthesis reaction is called the ''binding change mechanism'' and involves the active site of a β subunit cycling between three states. In the "open" state, ADP and phosphate enter the active site (shown in brown in the diagram). The protein then closes up around the molecules and binds them loosely – the "loose" state (shown in red). The enzyme then changes shape again and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly produced ATP molecule with very high
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle. In some bacteria and archaea, ATP synthesis is driven by the movement of sodium ions through the cell membrane, rather than the movement of protons. Archaea such as '' Methanococcus'' also contain the A1Ao synthase, a form of the enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP synthase subunits. It is possible that, in some species, the A1Ao form of the enzyme is a specialized sodium-driven ATP synthase, but this might not be true in all cases.


Oxidative phosphorylation - energetics

The transport of electrons from redox pair NAD+/ NADH to the final redox pair 1/2 O2/ H2O can be summarized as 1/2 O2 + NADH + H+ → H2O + NAD+ The potential difference between these two redox pairs is 1.14 volt, which is equivalent to -52 kcal/mol or -2600 kJ per 6 mol of O2. When one NADH is oxidized through the electron transfer chain, three ATPs are produced, which is equivalent to 7.3 kcal/mol x 3 = 21.9 kcal/mol. The conservation of the energy can be calculated by the following formula Efficiency = (21.9 x 100%) / 52 = 42% So we can conclude that when NADH is oxidized, about 42% of energy is conserved in the form of three ATPs and the remaining (58%) energy is lost as heat (unless the chemical energy of ATP under physiological conditions was underestimated).


Reactive oxygen species

Molecular oxygen is a good terminal
electron acceptor An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. Electron acceptors are oxidizing agents. The electron accepting power of an electron acceptor is measured by its redox potential. In the ...
because it is a strong oxidizing agent. The reduction of oxygen does involve potentially harmful intermediates. Although the transfer of four electrons and four protons reduces oxygen to water, which is harmless, transfer of one or two electrons produces
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
or
peroxide In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
anions, which are dangerously reactive. These
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
and their reaction products, such as the
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
radical, are very harmful to cells, as they oxidize proteins and cause
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, ...
s in
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. This cellular damage may contribute to
disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
and is proposed as one cause of
aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
. The cytochrome c oxidase complex is highly efficient at reducing oxygen to water, and it releases very few partly reduced intermediates; however small amounts of superoxide anion and peroxide are produced by the electron transport chain. Particularly important is the reduction of coenzyme Q in complex III, as a highly reactive ubisemiquinone free radical is formed as an intermediate in the Q cycle. This unstable species can lead to electron "leakage" when electrons transfer directly to oxygen, forming superoxide. As the production of reactive oxygen species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP production against oxidant generation. For instance, oxidants can activate
uncoupling protein An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from the ...
s that reduce membrane potential. To counteract these reactive oxygen species, cells contain numerous
antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
systems, including antioxidant
vitamin Vitamins are Organic compound, organic molecules (or a set of closely related molecules called vitamer, vitamers) that are essential to an organism in small quantities for proper metabolism, metabolic function. Nutrient#Essential nutrients, ...
s such as
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
and
vitamin E Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
, and antioxidant enzymes such as
superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
,
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting ...
, and peroxidases, which detoxify the reactive species, limiting damage to the cell.


In hypoxic/anoxic conditions

As
oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
is fundamental for oxidative phosphorylation, a shortage in O2 level can alter ATP production rates. The proton motive force and ATP production can be maintained by intracellular acidosis. Cytosolic protons that have accumulated with ATP hydrolysis and
lactic acidosis Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and lo ...
can freely diffuse across the mitochondrial outer-membrane and acidify the inter-membrane space, hence directly contributing to the proton motive force and ATP production. When exposed to hypoxia/anoxia (no oxygen), most animals will see damage done to their mitochondria. From some species, these conditions can happen due to environmental variables, such as low tides, low temperatures, or general living conditions, like living in a hypoxic underground burrow. In humans, these conditions are commonly met in medical emergencies such as
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
s,
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
, and
asphyxia Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects all the tissues and organs, some more rapidly than others. There are m ...
. Despite this, or perhaps due to it, some species have developed their own defense mechanisms against anoxia/hypoxia, as well as during reperfusion/reoxygenation. These mechanisms are diverse and differ between
endotherm An endotherm (from Greek ἔνδον ''endon'' "within" and θέρμη ''thermē'' "heat") is an organism that maintains its body at a metabolically favorable temperature, largely by the use of heat released by its internal bodily functions inst ...
s and
ectotherm An ectotherm (), more commonly referred to as a "cold-blooded animal", is an animal in which internal physiological sources of heat, such as blood, are of relatively small or of quite negligible importance in controlling body temperature.Dav ...
s and can differ even at the species level.


Endotherms


Hypoxia/anoxia intolerance

Most mammals and birds are intolerant to low/no oxygen conditions. For the heart, in the absence of oxygen, the first four complexes of the electron transport chain decrease in activity. This will lead to protons leaking through the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
without complexes I, III, and IV pushing protons back through to maintain the proton gradient. There is also electron leak (an event where electrons leak out of the electron transport chain), which happens because
NADH dehydrogenase NADH dehydrogenase is an enzyme that converts nicotinamide adenine dinucleotide (NAD) from its reduced form (NADH) to its oxidized form (NAD+). Members of the NADH dehydrogenase family and analogues are commonly systematically named using the f ...
within Complex I becomes damaged, which allows for the production of ROS (
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
) during ischemia. This will lead to the reversing of Complex V, which forces protons from the
matrix Matrix (: matrices or matrixes) or MATRIX may refer to: Science and mathematics * Matrix (mathematics), a rectangular array of numbers, symbols or expressions * Matrix (logic), part of a formula in prenex normal form * Matrix (biology), the m ...
back into the inner membrane space, against their
concentration gradient Fick's laws of diffusion describe diffusion and were first posited by Adolf Fick in 1855 on the basis of largely experimental results. They can be used to solve for the diffusion coefficient, . Fick's first law can be used to derive his second ...
. Forcing protons against their concentration gradient requires energy, so Complex V uses up ATP as an energy source.


Reoxygenation of intolerant animals

When oxygen re-enters the system, animals are faced with a different set of problems. Since ATP was used up during the anoxic period, it leads to a lack of ADP within the system. This is due to ADP's natural degradation into AMP, resulting in ADP being drained from the system. With no ADP in the system, Complex V is unable to start, meaning the protons will not flow through it to enter the matrix. Due to Complex V's reversal during anoxia, the proton gradient has become hyperpolarized (where the proton gradient is highly positively charged). Another factor in this problem is that
succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into Fuma ...
built up during anoxia, so when oxygen is reintroduced, succinate donates electrons to
Complex II Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...
. The hyperpolarized gradient and succinate buildup leads to reverse electron transport, causing
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, which can lead to cellular damage and diseases.


Hypoxia/anoxia tolerance

The naked mole rat ( ''Heterocephalus glaber'') is a hypoxia-tolerant species that sleeps in deep burrows and in large colonies. The depth of these burrows reduces access to oxygen, and sleeping in large groups will deplete the area of oxygen quicker than usual, leading to hypoxia. The naked mole rat has the unique ability to survive low oxygen conditions for no less than several hours, and zero oxygen conditions for 18 minutes. One of the ways of combatting hypoxia in the brain is decreasing the reliance on oxygen for ATP production, achieved by decreased respiration rates and proton leak.


Reoxygenation of tolerant animals

Hypoxia/anoxia tolerant species handle ROS production during reoxygenation better than the intolerant. In the cortex of the naked mole rats, they show better homeostasis of ROS production than intolerant species and seem to lack the burst of ROS that typically comes with reoxygenation.


Ectotherms


Hypoxia/anoxia intolerance

Research on intolerant ectotherms is more limited than on tolerant ectotherms and intolerant endotherms, but it is shown that anoxia/hypoxia intolerance is different in terms for how long the intolerant survive as opposed to the tolerant between endotherms and ectotherms. While intolerant endotherms only last minutes, intolerant ectotherms can last hours, such as subtidal scallops ('' Argopecten irradians''). This difference in intolerance could be due to a couple of different factors. One advantage is that the ectothermic inner mitochondrial membrane is less leaky, so less protons will leak through the inner membrane due to differences in the
phospholipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a l ...
composition. Another advantage ectotherms tend to have in this category is an ability for their mitochondria to properly function in a wide range of temperatures, such as the western fence lizard ('' Sceloporus occidentalis).'' While western fence lizards are not considered a hypoxia-tolerant animal, they still showed less temperature sensitivity in their mitochondria than mice mitochondria.


Reoxygenation of intolerant animals

While it is unclear how reoxygenation affects intolerant ectotherms at the mitochondrial level, there is some research showing how some of them respond. In the hypoxia-sensitive shovelnose ray ('' Aptychotrema rostrata),'' it is shown that ROS production is lower upon reoxygenation compared to rays only exposed to normoxia (normal oxygen levels). This differs from the hypoxia-sensitive endotherm, which would see an increase in ROS production. However, the ray's levels were still higher than the more hypoxia-tolerant Epaulette shark ('' Hemiscyllum ocellatum''), which potentially sees hypoxia due to the bouts of low tides that can be seen in reef platforms. Subtidal scallops will see both a decrease in maximal respiration and a depolarization of the membrane during reoxygenation.


Hypoxia/anoxia tolerance

Hypoxia/Anoxia tolerant ectotherms have shown unique strategies for surviving anoxia. Pond turtles, such as the painted turtle (''
Chrysemys picta bellii The painted turtle (''Chrysemys picta'') is the most widespread native turtle of North America. It lives in relatively slow-moving fresh waters, from southern Canada to northern Mexico, and from the Atlantic to the Pacific. They have been shown ...
''), will experience anoxia during winter while they overwinter at the bottom of frozen ponds. In their cardiac mitochondria, the reversing of Complex V, the usage of ATP, and the build-up of succinate are all prevented during anoxia. Crucian carps ('' Carassius carassius'') also overwinter in frozen ponds and show no loss membrane potential in their cardiac mitochondria during anoxia, but this relies on complexes I and III to be active.


Reoxygenation of tolerant animals

Pond turtles are able to completely avoid ROS production upon reoxygenation. However, crucian carp cannot and are unable to prevent the death of brain cells upon reoxygenation.


Inhibitors

There are several well-known
drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
s and
toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
s that inhibit oxidative phosphorylation. Although any one of these toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest of the process. For example, if oligomycin inhibits ATP synthase, protons cannot pass back into the mitochondrion. As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD+ falls below the concentration that these enzymes can use. Many site-specific inhibitors of the electron transport chain have contributed to the present knowledge of mitochondrial respiration. Synthesis of ATP is also dependent on the electron transport chain, so all site-specific inhibitors also inhibit ATP formation. The fish poison
rotenone Rotenone is an odorless, colorless, crystalline isoflavone. It occurs naturally in the seeds and stems of several plants, such as the jicama vine, and in the roots of several other members of the Fabaceae. It was the first-described member of the ...
, the barbiturate drug amytal, and the antibiotic piericidin A inhibit NADH and coenzyme Q. Carbon monoxide, cyanide, hydrogen sulphide and azide effectively inhibit cytochrome oxidase. Carbon monoxide reacts with the reduced form of the cytochrome while cyanide and azide react with the oxidised form. An antibiotic, antimycin A, and British anti-Lewisite, an antidote used against chemical weapons, are the two important inhibitors of the site between cytochrome B and C1. Not all inhibitors of oxidative phosphorylation are toxins. In
brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
, regulated proton channels called
uncoupling protein An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from the ...
s can uncouple respiration from ATP synthesis. This rapid respiration produces heat, and is particularly important as a way of maintaining
body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
for
hibernating Hibernation is a state of minimal activity and metabolic reduction entered by some animal species. Hibernation is a seasonal heterothermy characterized by low body-temperature, slow breathing and heart-rate, and low metabolic rate. It is most ...
animals, although these proteins may also have a more general function in cells' responses to stress.


History

The field of oxidative phosphorylation began with the report in 1906 by Arthur Harden of a vital role for phosphate in cellular
fermentation Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
, but initially only sugar phosphates were known to be involved. However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by Herman Kalckar, confirming the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941. Later, in 1949, Morris Friedkin and
Albert L. Lehninger Albert Lester Lehninger (February 17, 1917 – March 4, 1986) was an American chemist in the field of Biological thermodynamics, bioenergetics. He made fundamental contributions to the current understanding of metabolism at a molecular level. In ...
proved that the coenzyme NADH linked metabolic pathways such as the citric acid cycle and the synthesis of ATP. The term ''oxidative phosphorylation'' was coined by in 1939. For another twenty years, the mechanism by which ATP is generated remained mysterious, with scientists searching for an elusive "high-energy intermediate" that would link oxidation and phosphorylation reactions. This puzzle was solved by Peter D. Mitchell with the publication of the chemiosmotic theory in 1961. At first, this proposal was highly controversial, but it was slowly accepted and Mitchell was awarded a
Nobel prize The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...
in 1978. Subsequent research concentrated on purifying and characterizing the enzymes involved, with major contributions being made by David E. Green on the complexes of the electron-transport chain, as well as Efraim Racker on the ATP synthase. A critical step towards solving the mechanism of the ATP synthase was provided by
Paul D. Boyer Paul Delos Boyer (July 31, 1918 – June 2, 2018) was an American biochemist, analytical chemist, and a professor of chemistry at University of California, Los Angeles (UCLA). He shared the 1997 Nobel Prize in Chemistry for research on the " enz ...
, by his development in 1973 of the "binding change" mechanism, followed by his radical proposal of rotational catalysis in 1982. More recent work has included structural studies on the enzymes involved in oxidative phosphorylation by John E. Walker, with Walker and Boyer being awarded a Nobel Prize in 1997.


See also

* Respirometry * TIM/TOM Complex


Notes


References


Further reading


Introductory

* * *


Advanced

* * * *


General resources


Animated diagrams illustrating oxidative phosphorylation
Wiley and Co ''Concepts in Biochemistry''
On-line biophysics lectures
Antony Crofts,
University of Illinois at Urbana–Champaign The University of Illinois Urbana-Champaign (UIUC, U of I, Illinois, or University of Illinois) is a public land-grant research university in the Champaign–Urbana metropolitan area, Illinois, United States. Established in 1867, it is the f ...

ATP Synthase
Graham Johnson


Structural resources

* PDB molecule of the month:
ATP synthase




*Interactive molecular models at Universidade Fernando Pessoa:
NADH dehydrogenase






{{DEFAULTSORT:Oxidative Phosphorylation Cellular respiration Exercise biochemistry Integral membrane proteins Metabolism Redox