Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as a leukodystrophy in two siblings with Leigh syndrome

Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T → C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T → C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

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Cytochrome aa3 in facultatively aerobic and hyperthermophilic archaeon Pyrobaculum oguniense

Canadian Journal of Microbiology ◽

10.1139/w05-040 ◽

2005 ◽

Vol 51 (8) ◽

pp. 621-627 ◽

Cited By ~ 4

Author(s):

Takuro Nunoura ◽

Yoshihiko Sako ◽

Takayoshi Wakagi ◽

Aritsune Uchida

Keyword(s):

Oxygen Consumption ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Gene Product ◽

Respiratory Chain ◽

Oxidase Activity ◽

Terminal Oxidase ◽

Hyperthermophilic Archaeon ◽

Consumption Activity ◽

Copper Oxidase

We partially purified and characterized the cytochrome aa3 from the facultatively aerobic and hyperthermophilic archaeon Pyrobaculum oguniense. This cytochrome aa3 showed oxygen consumption activity with N, N, N′, N′-tetramethyl-1,4-phenylenediamine and ascorbate as substrates, and also displayed bovine cytochrome c oxidase activity. These enzymatic activities of cytochrome aa3 were inhibited by cyanide and azide. This cytochrome contained heme As, but not typical heme A. An analysis of trypsin-digested fragments indicated that 1 subunit of this cytochrome was identical to the gene product of subunit I of the SoxM-type heme – copper oxidase (poxC). This is the first report of a terminal oxidase in hyperthermophilic crenarchaeon belonging to the order Thermoproteales.Key words: aerobic respiratory chain, terminal oxidase, Archaea, hyperthermophile, Pyrobaculum.

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Pathology of Mitochondrial Encephalomyopathies

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100003929 ◽

2005 ◽

Vol 32 (2) ◽

pp. 152-166 ◽

Cited By ~ 60

Author(s):

Harvey B. Sarnat ◽

José Marín-García

Keyword(s):

Cytochrome C ◽

Succinate Dehydrogenase ◽

Cytochrome C Oxidase ◽

Oxidase Activity ◽

Morphological Evidence ◽

Regular Feature ◽

Complex Iv ◽

Genetic Studies ◽

Mitochondrial Encephalomyopathies ◽

Mitochondrial Cytopathy

ABSTRACT:Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

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Cytochrome c Oxidase (Complex IV)

Encyclopedia of Biophysics ◽

10.1007/978-3-642-16712-6_29 ◽

2013 ◽

pp. 423-426

Author(s):

Shelagh Ferguson-Miller

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Complex Iv

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Effect of Deficiency of Cytochrome C Oxidase Assembly Peptide Cox17p on Mitochondrial Functions and Respiratory-Chain in Mice

Peptides: The Wave of the Future ◽

10.1007/978-94-010-0464-0_372 ◽

2001 ◽

pp. 795-796

Author(s):

Yoshinori Takahashi ◽

Koichiro Kako ◽

Hidenori Arai ◽

Akio Takehara ◽

Eisuke Munekata

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Respiratory Chain ◽

Mitochondrial Functions

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The Lebanese Allele in the PET100 Gene: Report on Two New Families with Cytochrome c Oxidase Deficiency

Journal of Pediatric Genetics ◽

10.1055/s-0039-1685172 ◽

2019 ◽

Vol 08 (03) ◽

pp. 172-178 ◽

Cited By ~ 1

Author(s):

Hicham Mansour ◽

Sandra Sabbagh ◽

Sami Bizzari ◽

Stephany El-Hayek ◽

Eliane Chouery ◽

...

Keyword(s):

Cytochrome C ◽

Lactic Acidosis ◽

Developmental Delay ◽

Cytochrome C Oxidase ◽

Brain Magnetic Resonance Imaging ◽

Global Developmental Delay ◽

Mitochondrial Complex ◽

Oxidase Deficiency ◽

Complex Iv ◽

Cytochrome C Oxidase Deficiency

AbstractCytochrome c oxidase deficiency is caused by mutations in any of at least 30 mitochondrial and nuclear genes involved in mitochondrial complex IV biogenesis and structure, including the recently identified PET100 gene. Here, we report two families, of which one is consanguineous, with two affected siblings each. In one family, the siblings presented with developmental delay, seizures, lactic acidosis, abnormal brain magnetic resonance imaging, and low muscle mitochondrial complex IV activity at 30%. In the other family, the two siblings, now deceased, had a history of global developmental delay, failure to thrive, muscular hypotonia, seizures, developmental regression, respiratory insufficiency, and lactic acidosis. By whole exome sequencing, a missense mutation in exon 1 of the PET100 gene (c.3G > C; [p.Met1?]) was identified in both families. A review of the clinical description and literature is discussed, highlighting the importance of this variant in the Lebanese population.

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Steady-state levels of subunits of respiratory chain enzymes: clues to the primary genetic defect in cytochrome c oxidase deficiencies

Genetics Research ◽

10.1017/s0016672398433305 ◽

1998 ◽

Vol 72 (1) ◽

pp. 59-72

Author(s):

SION WILLIAMS ◽

J. W. TAANMAN ◽

H. R. SCHOLTE ◽

A. SCHAPIRA

Keyword(s):

Steady State ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Respiratory Chain ◽

Genetic Defect ◽

Steady State Levels

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Heteroplasmic Point Mutations of Mitochondrial DNA Affecting Subunit I of Cytochrome c Oxidase in Two Patients With Acquired Idiopathic Sideroblastic Anemia

Blood ◽

10.1182/blood.v90.12.4961 ◽

1997 ◽

Vol 90 (12) ◽

pp. 4961-4972 ◽

Cited By ~ 120

Author(s):

Norbert Gattermann ◽

Stefan Retzlaff ◽

Yan-Ling Wang ◽

Götz Hofhaus ◽

Jürgen Heinisch ◽

...

Keyword(s):

Bone Marrow ◽

Mitochondrial Dna ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Respiratory Chain ◽

Ferric Iron ◽

Point Mutations ◽

Polymorphism Analysis ◽

Sideroblastic Anemia ◽

Wide Range

Abstract Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T → C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T → C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

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