Cytochrome c oxidase assembly factor COX14 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 ...

that in humans is encoded by the COX14

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 ...

. This gene encodes a small single-pass

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

that localizes to

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 ...

. This

may play a role in coordinating the early steps 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 ...

(COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the

holoenzyme 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 ...

Mutations 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, mitosi ...

in this gene have been associated with

complex IV 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 respiratory ele ...

deficiency.

Alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

results in multiple

transcript variants Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

Structure

The ''COX14'' gene is located on the

q arm In genetics, a locus (: loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total numb ...

chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

at position 13.12 and it spans 8,476 base pairs. The ''COX14'' gene produces a 6.6 kDa protein composed of 57

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 ...

. COX14 is a component of the enzyme MITRAC (mitochondrial

translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...

regulation assembly intermediate of

complex) complex, and the structure contains a central transmembrane domain.

Function

The ''COX14'' gene encodes for a core

component of the MITRAC (mitochondrial

regulation assembly intermediate of

complex) complex, which is required for the proper regulation of

assembly.

Complex IV 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 respiratory ele ...

of the

mitochondrial respiratory 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 this ...

is essential in catalyzing the oxidation of cytochrome c by

molecular oxygen There are several known allotropes of oxygen. The most familiar is molecular oxygen (), present at significant levels in Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the highly reactive ozone (). Others are: * Atomic ...

. COX14 has been shown to contribute to the early stages of

assembly by coelution with

COX1 Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the ''MT-CO1'' gene in eukaryotes. The gene is also called ''COX1'', ''CO1'', or ''COI''. Cytochrome c oxidase ...

and COX4 for nucleation of the assembly. The protein participates in the coupling synthesis of

followed by an assembly of nascent subunits into the holoenzyme

. The knockdown of the protein COX14 involving

small interfering RNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA, double-stranded non-coding RNA, non-coding RNA, RNA molecules, typically 20–24 base pairs in length, similar to microR ...

in regular human

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

has been shown to result in a

defect with reduced activity.

Clinical significance

Variants of ''COX14'' have been associated with the

deficiency, a deficiency in an enzyme complex of the

which catalyzes the oxidation of cytochrome c utilizing

. The deficiency is characterized by

heterogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...

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 A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. It differs from a localized disease, which is a disease affecting only part of the body (e.g., a mouth ulcer). Examples * Mastocytosis, incl ...

affecting several tissues and organs. Other Clinical Manifestations include

hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...

hepatomegaly Hepatomegaly is enlargement of the liver. It is a non-specific sign (medicine), medical sign, having many causes, which can broadly be broken down into infection, hepatic tumours, and metabolic disorder. Often, hepatomegaly presents as an abdomin ...

and

liver dysfunction Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground glas ...

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 Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includ ...

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...

developmental delay The term developmental delay can refer to: *Global developmental delay, an umbrella term used when children are significantly delayed in two or more areas of development *Specific developmental disorder, a classification of disorders characterize ...

, delayed

motor development A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or ...

and

mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

. A mutation in the homozygous

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

c.88G>A in the ''COX14'' gene has resulted in the dysfunction of

assembly and an unstable nascent enzyme complex.

Interactions

Like COA3, COX14 is a key component of the MITRAC (mitochondrial

regulation assembly intermediate of

complex) complex. In addition, it has interactions with proteins such as COX17,

LMNA Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, r ...

, COA3, SPPL2B, and others.

Structure

Function

Clinical significance

Interactions

References

Further reading