Cytochrome c oxidase II is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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 that is encoded by the MT-CO2

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of

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 ...

. It is also one of the three

mitochondrial DNA Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...

(mtDNA) encoded subunits ( MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV.

Structure

In humans, the ''MT-CO2'' gene is located on the p arm of

at position 12 and it spans 683 base pairs. The ''MT-CO2'' gene produces a 25.6 kDa protein composed of 227

amino acids 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 Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

. MT-CO2 is a subunit of the enzyme

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 ...

() (Complex IV), an oligomeric enzymatic

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

of the mitochondrial respiratory chain involved in the transfer of

electrons The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

from cytochrome c to

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 ...

. In eukaryotes this

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 ...

is located in the mitochondrial inner membrane; in aerobic

prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

it is found in the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. The enzyme complex consists of 3-4 subunits (

) to up to 13 polypeptides (mammals). The N-terminal domain of cytochrome C oxidase contains two transmembrane alpha-helices. The structure of MT-CO2 is known to contain one redox center and a binuclear copper A center (CuA). The CuA is located in a conserved

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 ...

loop at 196 and 200

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 ...

positions and conserved

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

at 204. Several bacterial MT-CO2 have a C-terminal extension that contains a covalently bound haem c.

Function

The ''MT-CO2'' gene encodes for the second subunit of

(complex IV), a component of the mitochondrial respiratory chain that catalyzes the reduction of

water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...

. MT-CO2 is one of the three subunits which are responsible for the formation of the functional core of the

. MT-CO2 plays an essential role in the transfer of electrons from cytochrome c to the bimetallic center of the catalytic subunit 1 by utilizing its binuclear copper A center. It contains two adjacent transmembrane regions in its

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and the major part of the protein is exposed to the periplasmic or to the mitochondrial

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 ...

, respectively. MT-CO2 provides the substrate-binding site and contains the binuclear copper A center, probably the primary acceptor in cytochrome c oxidase.

Clinical significance

Mitochondrial complex IV deficiency

Variants of ''MT-CO2'' have been associated with the

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 ...

l Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain that catalyzes the oxidation of cytochrome c utilizing molecular oxygen. The deficiency is characterized by heterogeneous phenotypes ranging from isolated

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

, muscle weakness, exercise intolerance,

developmental disability Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...

, delayed motor development and mental retardation. Mutations of ''MT-CO2'' is also known to cause Leigh's disease, which may be caused by an abnormality or deficiency of cytochrome oxidase. A wide range of symptoms have been found in patients with pathogenic mutations in the ''MT-CO2'' gene with the

l Complex IV deficiency. A deletion mutation of a single nucleotide (7630delT) in the gene has been found to cause symptoms of reversible

aphasia Aphasia, also known as dysphasia, is an impairment in a person's ability to comprehend or formulate language because of dysfunction in specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine, but aph ...

, right

hemiparesis Hemiparesis, also called unilateral paresis, is the weakness of one entire side of the body (''wikt:hemi-#Prefix, hemi-'' means "half"). Hemiplegia, in its most severe form, is the complete paralysis of one entire side of the body. Either hemipar ...

, hemianopsia, exercise intolerance, progressive mental impairment, and short stature. Furthermore, a patient with a nonsense mutation (7896G>A) of the gene resulted in phenotypes such as

short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...

, low

weight In science and engineering, the weight of an object is a quantity associated with the gravitational force exerted on the object by other objects in its environment, although there is some variation and debate as to the exact definition. Some sta ...

, microcephaly, skin abnormalities, severe

, and normal

reflexes In biology, a reflex, or reflex action, is an involuntary, unplanned sequence or action and nearly instantaneous response to a Stimulus (physiology), stimulus. Reflexes are found with varying levels of complexity in organisms with a nervous s ...

. A novel heteroplasmic mutation (7587T>C) which altered the initiation codon of the ''MT-CO2'' gene in patients have shown clinical manifestations such as progressive gait

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, cognitive impairment, bilateral optic atrophy, pigmentary retinopathy, a decrease in color vision, and mild distal- muscle wasting.

Others

Juvenile

, encephalopathy, lactic acidosis, and

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 ...

have also been associated with mutations in the ''MT-CO2'' gene.

Interactions

MT-CO2 is known to interact with cytochrome c by the utilization of a lysine ring around the carboxyl containing heme edge of cytochrome c in MT-CO2, including glutamate 129, aspartate 132, and glutamate 19.