Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:10746566, PubMed:24781757). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate (By similarity). Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate

Mitochondrion inner membrane

Mitochondrial complex II deficiency, nuclear type 1

A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. MC2DN1 inheritance is autosomal recessive.

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.

Subunit 8, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain (PubMed:37244256). ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel (PubMed:37244256). These two domains are linked by a central stalk rotating inside

Mitochondrion membrane

Mitochondrial complex V deficiency, mitochondrial 2

A mitochondrial disorder with heterogeneous clinical manifestations including neuropathy, ataxia, hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy can present with negligible to extreme hypertrophy, minimal to extensive fibrosis and myocyte disarray, absent to severe left ventricular outflow tract obstruction, and distinct septal contours/morphologies with extremely varying clinical course.

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

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.

Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:15250827, PubMed:8344246, PubMed:8644732). Essential for the catalytic activity and assembly of complex I (PubMed:15250827, PubMed:8344246, PubMed:8644732)

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

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.

Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). Required for the formation of 5-taurinomethyl-2-thiouridine (tm5s2U) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln) at the wobble position. ATP is required to activate the C2 atom of the wobble base

Mitochondrion

Deafness, aminoglycoside-induced

A form of sensorineural deafness characterized by moderate-to-profound hearing loss and mitochondrial inheritance. It is induced by exposure to aminoglycosides.

Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:15250827). Essential for the catalytic activity and assembly of complex I (PubMed:15250827)

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.

AMP deaminase plays a critical role in energy metabolism

Adenosine monophosphate deaminase deficiency erythrocyte type

A metabolic disorder due to lack of activity of the erythrocyte isoform of AMP deaminase. It is a clinically asymptomatic condition characterized by a 50% increase in steady-state levels of ATP in affected cells. Individuals with complete deficiency of erythrocyte AMP deaminase are healthy and have no hematologic disorders.

Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:1959619). Essential for the catalytic activity and assembly of complex I (PubMed:1959619, PubMed:26929434)

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.

Involved in the regulation of mitochondrial distribution and morphology (PubMed:17349998, PubMed:28544275, PubMed:28554942). Required for mitochondrial fusion and mitochondrial network formation (PubMed:28544275, PubMed:28554942)

Mitochondrion outer membraneCytoplasm

Myopathy, mitochondrial, and ataxia

A neuromuscular disorder characterized by muscle weakness and atrophy, ataxia, poor growth, delayed motor development, dysdiadochokinesia, dysmetria and additional neurologic features. Some patients show skeletal and endocrine anomalies, as well as behavioral psychiatric manifestations. MMYAT transmission pattern is consistent with autosomal dominant inheritance in some families, and autosomal recessive inheritance in others.

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:1550553, PubMed:29915090, PubMed:30850536, PubMed:8135828, PubMed:31604922). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specific

MitochondrionMitochondrion inner membrane

Mitochondrial trifunctional protein deficiency 1

An autosomal recessive metabolic disorder of long-chain fatty acid oxidation, biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. The disease phenotype ranges from a fatal form characterized by early-onset cardiomyopathy, cardiac failure and early death to less severe, late-onset forms with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy as key features.

Electron donor, of the core iron-sulfur cluster (ISC) assembly complex, that acts to reduce the persulfide into sulfide during [2Fe-2S] clusters assembly on the scaffolding protein ISCU (PubMed:28001042). The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis (By similarity). This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces pe

MitochondrionMitochondrion matrix

Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy

An autosomal recessive neuromuscular disorder characterized by childhood onset of recurrent episodes of proximal weakness and myalgia often precipitated by exercise, infections or low temperature. Additional features are optic atrophy, axonal polyneuropathy, and reversible or partially reversible leukoencephalopathy.

Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:26925370, PubMed:27604842). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate (By similarity). Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate (By similarity)

Mitochondrion inner membrane

Pheochromocytoma/paraganglioma syndrome 4

A form of pheochromocytoma/paraganglioma syndrome, a tumor predisposition syndrome characterized by the development of neuroendocrine tumors, usually in adulthood. Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells in the adrenal medulla. Paragangliomas develop from sympathetic paraganglia in the thorax, abdomen, and pelvis, as well as from parasympathetic paraganglia in the head and neck. PPGL4 inheritance is autosomal dominant.

Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:10482792, PubMed:9533030). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate (By similarity). Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate

Mitochondrion inner membrane

Pheochromocytoma/paraganglioma syndrome 1

A form of pheochromocytoma/paraganglioma syndrome, a tumor predisposition syndrome characterized by the development of neuroendocrine tumors, usually in adulthood. Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells in the adrenal medulla. Paragangliomas develop from sympathetic paraganglia in the thorax, abdomen, and pelvis, as well as from parasympathetic paraganglia in the head and neck. PPGL1 inheritance is autosomal dominant.

Assembly factor for cytochrome c oxidase (respiratory chain complex IV) (PubMed:21457908, PubMed:35750769). Stabilizes an early formation of cytochrome c oxidase assembly factors, until it is displaced by the metallochaperone copper-delivery protein COX17 (PubMed:35750769)

Mitochondrion intermembrane space

Mitochondrial complex IV deficiency, nuclear type 9

An autosomal recessive, infantile disorder with a fatal course in the first weeks of life, and characterized by hypertrophic cardiomyopathy and mitochondrial complex IV deficiency. Postmortem microscopic investigations show accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation.

Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary for adequate mitochondrial function (PubMed:12930833, PubMed:19164547, PubMed:19700766, PubMed:26908608, PubMed:33096711). Its role in cellular physiology is to improve mitochondrial performance (PubMed:32234310). CL is critical for the coassembly of lipids and p

Mitochondrion outer membraneMitochondrion inner membraneMitochondrion membraneCytoplasm

Barth syndrome

An X-linked disease characterized by dilated cardiomyopathy with endocardial fibroelastosis, a predominantly proximal skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly excess of 3-methylglutaconic acid. Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.

May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure

Mitochondrion intermembrane space

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2

A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis.

Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix (PubMed:11687801, PubMed:9989599). In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on TK2 and DGUOK (PubMed:9989599). Widely used as target of antiviral and chemotherapeutic agents (PubMed:9989599)

Mitochondrion

Mitochondrial DNA depletion syndrome 2

A disorder due to mitochondrial dysfunction characterized by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later onset of a slowly progressive myopathy.

Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine (PubMed:11687801, PubMed:17073823, PubMed:23043144, PubMed:8692979, PubMed:8706825). In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on DGUOK and TK2. Phosphorylates certain nucleoside analogs (By similarity). Widely used as target of antiviral and chemotherapeutic agents

Mitochondrion

Mitochondrial DNA depletion syndrome 3

A disorder due to mitochondrial dysfunction characterized by onset in infancy of progressive liver failure, hypoglycemia, increased lactate in body fluids, and neurologic abnormalities including hypotonia, encephalopathy, peripheral neuropathy. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes and mtDNA depletion.

ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By si

Mitochondrion inner membraneMembrane

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides

Cytoplasm

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6

A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. Ragged red fibers are seen on muscle biopsy.

Endonuclease that specifically degrades the RNA of RNA-DNA hybrids (PubMed:10497183). Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II (PubMed:21700224)

Cytoplasm

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2

A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB2 patients manifest exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency.

Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage

CytoplasmNucleus

Mitochondrial DNA depletion syndrome 8A

A disorder due to mitochondrial dysfunction characterized by various combinations of neonatal hypotonia, neurological deterioration, respiratory distress, lactic acidosis, and renal tubulopathy.

Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol (PubMed:19465911, PubMed:24954417). Promotes maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic dimer, protecting i

Mitochondrion matrix

Mitochondrial complex II deficiency, nuclear type 2

A form of mitochondrial complex II deficiency, a disorder with heterogeneous clinical manifestations. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. MC2DN2 inheritance is autosomal recessive.

FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen May act as an auto

Mitochondrion intermembrane spaceMitochondrionCytoplasmSecreted

Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay

A disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay.

Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the release of lipid second messengers and growth factors (PubMed:10744668, PubMed:10833412, PubMed:15695510, PubMed:15908428, PubMed:17213206, PubMed:18171998, PubMed:28442572). Hydrolyzes phosphatidylethanolamine, phosphatidylcholine and probably phosphatidylinosi

Endoplasmic reticulum membraneMitochondrion membranePeroxisome membrane

Mitochondrial myopathy with lactic acidosis

An autosomal recessive disorder characterized by progressive muscle weakness, hypotonia, seizures, poor weight gain, lactic acidosis, and elevated serum pyruvate concentration. Some patients manifest growth failure and moderate neural deafness.

Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO) (PubMed:12474143). Heme A is synthesized from heme B by two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). HAS catalyzes the conversion of heme O to heme A by two successive hydroxylations of the methyl group at C8, in a reaction that involves matrix ferredoxin and ferredoxin reductase. The first hydroxylation forms heme I, the

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 6

An autosomal recessive multisystem disorder with variable manifestations. Some patients present in the neonatal period with encephalomyopathic features, whereas others present later in the first year of life with developmental regression. Clinical features include microcephaly, encephalopathy, hypertrophic cardiomyopathy, persistent lactic acidosis, respiratory distress, hypotonia and seizures. Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels.

Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone

Mitochondrion inner membrane

Mitochondrial complex I deficiency, nuclear type 1

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.

Isoform 3 functions as a heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents. Isoform 1 is targeted to mitochondria, where it functions as a DNA ligase in mitochondrial base-excision DNA repair (PubMed:10207110, PubMed:24674627)

MitochondrionNucleus

Mitochondrial DNA depletion syndrome 20, MNGIE type

An autosomal recessive mitochondrial disorder characterized by severe gut dysmotility, muscle weakness and atrophy, neurological abnormalities including epilepsy, migraine, stroke-like episodes, learning difficulties or cognitive decline, and neurogenic bladder. Brain imaging usually shows diffuse leukoencephalopathy and may show cerebellar atrophy. Disease onset can range from infancy to the teenage years.

Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. Involved in Okazaki fragments processing by cleaving long flaps that escape FEN1: flaps that are longer than 27 nucleotides are coated by replication protein A complex (RPA), leading to recruit DNA2 which cleaves the flap until it is too short to bind RPA and becomes a substrate for FEN1. Also involved in 5'-end resection of DNA during double-strand break (DSB) repair: recruited by BLM and mediates the cleavage o

NucleusMitochondrion

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6

A disorder characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression.

Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Acts as an allosteric regulator of the holoenzyme activities. Enhances the polymerase activity and the processivity of POLG by increasing its interactions with the DNA template. Suppresses POLG exonucleolytic proofreading especially toward homopolymeric templates bearing mismatched termini. Binds to single-stranded DNA

MitochondrionMitochondrion matrix, mitochondrion nucleoid

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Mitochondrial helicase involved in mtDNA replication and repair (PubMed:12975372, PubMed:15167897, PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair (PubMed:27226550). Has DNA strand separation activity needed to form a processive replication fork for leading strand synthesis which is catalyzed by the formation of a replisome complex with POLG and mtSDB (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMe

Mitochondrion matrix, mitochondrion nucleoidMitochondrion inner membrane

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes

Mitochondrion matrix

Microcephaly, growth restriction, and increased sister chromatid exchange 2

An autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies.

Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr)

Mitochondrion matrix

Myopathy with lactic acidosis and sideroblastic anemia 2

A rare oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Affected individuals manifest sideroblastic anemia, progressive lethargy, muscle weakness, and exercise intolerance associated with persistent lactic acidemia.

Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs (PubMed:15772074, PubMed:24722331). Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA (PubMed:24722331). Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3' (PubMed:31477916, PubMed:35051350). Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at loca

MitochondrionNucleusCytoplasm

Myopathy with lactic acidosis and sideroblastic anemia 1

A rare oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Affected individuals manifest progressive muscle weakness, exercise intolerance, lactic acidosis, sideroblastic anemia and delayed growth.

May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis

Mitochondrial DNA depletion syndrome 1, MNGIE type

A multisystem disease associated with mitochondrial dysfunction. It is clinically characterized by onset between the second and fifth decades of life, ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, cachexia, peripheral neuropathy, and myopathy.

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:29915090, PubMed:30850536, PubMed:8135828). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (P

MitochondrionMitochondrion inner membraneMitochondrion outer membraneEndoplasmic reticulum

Mitochondrial trifunctional protein deficiency 2

An autosomal recessive metabolic disorder of long-chain fatty acid oxidation, biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. The disease phenotype ranges from a fatal form characterized by early-onset cardiomyopathy, cardiac failure and early death to less severe, late-onset forms with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy as key features.

Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Replicates both heavy and light strands of the circular mtDNA genome using a single-stranded DNA template, RNA primers and the four deoxyribonucleoside triphosphates as substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. Functionally interacts with TWNK and SSBP1 at the replication fork to form a highly processiv

MitochondrionMitochondrion matrix, mitochondrion nucleoid

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2 (PubMed:15229189, PubMed:17189203, PubMed:19336478, PubMed:35750769). Could also act as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2 (PubMed:19336478)

Mitochondrion inner membrane

Mitochondrial complex IV deficiency, nuclear type 2

An autosomal recessive, severe mitochondrial disorder characterized by hypotonia, global developmental delay, hypertrophic cardiomyopathy, lactic acidosis, gliosis, and neuronal loss in basal ganglia, brainstem and spinal cord. Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure.

Involved in the maturation of the mitochondrial respiratory chain complex IV subunit MT-CO2/COX2. Thereby, may regulate early steps of complex IV assembly. Mitochondrial respiratory chain complex IV or cytochrome c oxidase is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. May also be required for

Mitochondrion intermembrane space

Mitochondrial complex IV deficiency, nuclear type 13

An autosomal recessive, infantile disorder with a fatal course in the first weeks of life, characterized by hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, metabolic hypotonia, and mitochondrial complex IV deficiency.