Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:29355485, PubMed:29381136, PubMed:33169484). Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2) (PubMed:29355485, PubMed:29381136). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6 (PubMed:29381136). Probably facilitates MT-CO2/COX2 association w

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 22

An autosomal recessive mitochondrial disorder characterized by hypertrophic cardiomyopathy, encephalopathy, fatal lactic acidosis, and isolated complex IV deficiency.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 21

An autosomal recessive mitochondrial disorder with onset in infancy. MC4DN21 is characterized by congenital lactic acidosis, encephalopathy, global developmental delay, delayed speech, motor dysfunction, dystonia, and spasticity. Ataxia, peripheral neuropathy, and seizures may also occur. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency

A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and intellectual disability. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome.

Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Together with SCO2, involved in delivering copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15229189, PubMed:15659396, PubMed:16735468, PubMed:17189203, PubMed:19336478). Plays an important role in the regulation of copper homeostasis by controlling the abundance and cell membrane localization of copper transporter CTR1 (By similarity)

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 4

An autosomal recessive mitochondrial disorder characterized by hypotonia, encephalopathy, metabolic acidosis, poor feeding, hepatomegaly, and hypertrophic cardiomyopathy in some patients. Death occurs in infancy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 16

An autosomal recessive mitochondrial disorder with onset in infancy and variable manifestations. MC4DN16 features include feeding difficulties, poor overall growth, short stature, microcephaly, developmental regression, severe hypotonia, and seizures. Cerebral and cerebellar atrophy, and abnormal lesions in the basal ganglia can be observed on brain imaging. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Required for cytochrome c complex (COX) IV assembly and function Protects COX assembly from oxidation-induced degradation, COX being the terminal component of the mitochondrial respiratory chain

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 17

An autosomal recessive mitochondrial disorder with highly variable clinical manifestations and severity. Clinical features vary from acute neurometabolic decompensation in late infancy to subtle neurological signs presenting in adolescence. Encephalopathic episodes are characterized by acute loss of developmental milestones including ability to walk or sit, loss of speech, episodes with somnolence and seizure, and pyramidal signs rapidly evolving into spastic tetraparesis. The clinical course subsequently tends to stabilize and in several subjects marked recovery of neurological milestones is observed over time. Brain imaging shows a cavitating leukodystrophy, predominantly involving the posterior cerebral white matter and the corpus callosum in the acute stage, after which the abnormalities partially improve and then stabilize. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 18

An autosomal recessive, muscle-specific, mitochondrial disorder with onset in infancy. MC4DN18 is characterized by hypotonia, limb and facial muscle weakness, and high arched palate. Some patients have respiratory insufficiency at birth and cardiomyopathy. Patient skeletal muscle shows decreased levels and activity of mitochondrial respiratory complex IV.

Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1

Mitochondrion

Mitochondrial complex IV deficiency, nuclear type 8

An autosomal recessive mitochondrial disorder characterized by slowly progressive cognitive dysfunction, dystonia or visual impairment that appear after an uneventful early childhood. Additional features include gait difficulties, spasticity, dysarthria, hypotonia, and variable intellectual disability. Brain imaging shows white matter abnormalities in the basal ganglia. Serum lactate levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Plays an essential role in mitochondrial complex IV maturation and assembly

MembraneMitochondrionMitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 12

An autosomal recessive mitochondrial disorder with onset in early infancy. MC4DN12 features include poor overall growth, metabolic acidosis, profoundly delayed psychomotor development, seizures, hypotonia, and brain abnormalities. Death may occur in the first years of life. Serum lactate and creatine kinase levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Leber hereditary optic neuropathy

A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 20

An autosomal recessive mitochondrial disorder with onset in early infancy. MC4DN20 is characterized by pulmonary arterial hypertension, poor feeding, failure to thrive, hypotonia, delayed development, increased serum lactate and metabolic acidosis. Death in infancy occurs due to cardiorespiratory failure. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV.

Converts protoheme IX and farnesyl diphosphate to heme O

Mitochondrion membrane

Mitochondrial complex IV deficiency, nuclear type 3

An autosomal recessive mitochondrial disorder characterized by cytochrome c oxidase deficiency. Clinical features include muscle weakness, hypotonia, ataxia, ptosis, metabolic acidosis, poor feeding, delayed motor development, anemia, sensorineural hearing loss, and cardiomyopathy.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 7

An autosomal recessive mitochondrial disorder characterized by encephalomyopathy resulting in variable clinical manifestations. Features include muscle weakness, gait disturbances, neurodegeneration, cognitive decline, metabolic acidosis, feeding difficulties, poor overall growth, cortical visual impairment, and hypertrophic cardiomyopathy. Serum lactate levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Assembly factor for cytochrome c oxidase (respiratory chain complex IV, CIV) (PubMed:35750769). Probably acts as a metallochaperone that delivers copper to the copper B site of COX1 (PubMed:35750769)

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 23

A primary mitochondrial disease, a clinically heterogeneous group of disorders arising from dysfunction of the mitochondrial respiratory chain. MC4DN23 is an autosomal recessive form characterized by infantile-onset encephalopathy. Clinical features include brain atrophy, severe developmental delay, seizures, and dyskinetic movement abnormalities.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Leber hereditary optic neuropathy

A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes.

Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 1

An autosomal recessive disorder of the mitochondrial respiratory chain characterized by early-onset, rapidly progressive encephalopathy, neurodegeneration, and loss of motor and cognitive skills. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, poor eye contact, oculomotor abnormalities, as well as deafness, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia. Lactate levels in serum and cerebrospinal fluid are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death in childhood may occur, often due to central respiratory failure.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Exocrine pancreatic insufficiency dyserythropoietic anemia and calvarial hyperostosis

Patients present with pancreatic insufficiency, intestinal malabsorption, failure to thrive, and anemia soon after birth.

Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. Requires for coordination of the early steps of cytochrome c oxidase assembly with the synthesis of MT-CO1

Mitochondrion outer membrane

Mitochondrial complex IV deficiency, nuclear type 10

An autosomal recessive mitochondrial disorder that manifests with neonatal neurological and respiratory distress. Clinical features include facial dysmorphism, hypotelorism, microphthalmia, an ogival palate, and severe metabolic acidosis. Death occurs in early infancy. Autoptic examination reveals brain hypertrophy, diffuse alteration of white matter myelination, numerous cavities in the parieto-occipital region, brainstem and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for efficient translation of MT-CO1 and mitochondrial respiratory chain complex IV assembly

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 14

An autosomal recessive mitochondrial disorder with onset in early childhood. MC4DN14 is characterized by developmental delay, cognitive impairment, motor delay, abnormal gait, sensorimotor demyelinating polyneuropathy, exercise intolerance, obesity, and short stature. Serum lactate levels are marginally increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:23125284). Acts as a chaperone in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation, stabilizing the newly synthesized protein and presenting it to metallochaperones SCO1/2 which in turn facilitates the incorporation of the mature MT-CO2/COX2 into the assembling CIV holoenzyme (PubMed:24403053)

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 11

An autosomal recessive mitochondrial disorder with onset in childhood or adolescence. MC4DN11 is characterized by walking difficulties, cerebellar ataxia, dystonia, choreoathetotic movements and dysarthria. Additional features may include sensory axonal neuropathy, cerebellar atrophy, and mild speech delay. Cognitive function is normal. Serum lactate levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Mitochondrion

Mitochondrial complex IV deficiency, nuclear type 19

An autosomal recessive mitochondrial disorder with onset in infancy or early childhood. MC4DN19 is characterized by global developmental delay, impaired intellectual development, developmental regression, loss of acquired motor and language skills, and motor dysfunction. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over t

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 15

An autosomal recessive mitochondrial disorder with onset in infancy. MC4DN15 is characterized by global developmental delay, poor feeding, metabolic acidosis, short stature, microcephaly, proximal muscle weakness, and distal spasticity. Additional manifestations include scoliosis, primary pulmonary hypertension, refractory seizures, and inability to walk. Serum and CSF lactate levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.