Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial disorder is an inborn error of metabolism affecting the cellular respiratory chain. Defective energy production leads to a wide variety of clinical manifestations (ataxia, epilepsy, dementia, myopathy, polyneuropathy, retinal pigment anomalies, and cardiomyopathy with conduction anomalies). Hearing loss is a regular feature and is often the first clinical symptom. Audiologic data from 26 members of a family in three generations is presented. One of these patients was examined for the biochemical error. Respiratory study of muscle biopsy revealed a mild defect in the NADH-ubiquinone oxidoreductase step of the oxidative phosphorylation (complex I). The content of cytochrome aa3 (complex IV) was also reduced. Adult onset sensorineural hearing loss starting in the high frequency region progresses with a fairly constant speed in this family. A cochlear type of hearing loss is found in the less pronounced cases. Advanced cases present features of retrocochlear affection with decreasing speech recognition, elevated acoustic reflex thresholds, and increased ABR latency with derangement of potentials. Caloric sensitivity was unaffected.
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PMID:Audiologic findings in a family with mitochondrial disorder. 180 40

A case of mitochondrial encephalomyopathy (Kearns-Sayre syndrome) with corneal endothelial abnormality is reported. A 22-year-old woman had retinitis pigmentosa, external ophthalmoplegia, complete heart block, ataxia, muscle weakness, dementia, sensorineural hearing loss, and was of short stature. Renal dysfunction, diabetes mellitus, and amenorrhea were also observed. Biopsy revealed decreased cytochrome c oxidase (complex IV) activity in muscle mitochondria. The corneal endothelium examined by specular microscope showed decreased cell density, severe polymegathism, and pleomorphism in both eyes. To our knowledge, this is the first report concerning primary corneal endothelial abnormality in a case with mitochondrial encephalomyopathy. The corneal endothelium is one of the tissues that could be affected by the enzyme deficiency present in this disease.
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PMID:Corneal endothelium in a case of mitochondrial encephalomyopathy (Kearns-Sayre syndrome). 274 82

Presbycusis is a histologically and genetically heterogenous group of disorders, which lead to progressive, primarily sensorineural hearing loss with aging. Acquired mitochondrial DNA defects have been proposed as important determinants of aging, particularly in neuro-muscular tissues. The spiral ganglion and membranous labyrinth from archival temporal bones of 5 patients with presbycusis were examined for mutations within the mitochondrially-encoded cytochrome oxidase II gene. When compared to controls, results indicate that mitochondrial mutations in the peripheral auditory system occur commonly with age-related hearing loss, that there is great individual variability in both quantity and location of mutation accumulation, and that at least a proportion of presbycusis patients have a highly significant load of mutations in auditory tissue. This work supports the hypothesis that acquired mitochondrial mutations are a determinant of hearing loss in a subgroup of presbycusis patients.
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PMID:Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations. 928 97

Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
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PMID:Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism. 1590 51

A disulfide relay system (DRS) was recently identified in the yeast mitochondrial intermembrane space (IMS) that consists of two essential components: the sulfhydryl oxidase Erv1 and the redox-regulated import receptor Mia40. The DRS drives the import of cysteine-rich proteins into the IMS via an oxidative folding mechanism. Erv1p is reoxidized within this system, transferring its electrons to molecular oxygen through interactions with cytochrome c and cytochrome c oxidase (COX), thereby linking the DRS to the respiratory chain. The role of the human Erv1 ortholog, GFER, in the DRS has been poorly explored. Using homozygosity mapping, we discovered that a mutation in the GFER gene causes an infantile mitochondrial disorder. Three children born to healthy consanguineous parents presented with progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. The consequences of the mutation at the level of the patient's muscle tissue and fibroblasts were 1) a reduction in complex I, II, and IV activity; 2) a lower cysteine-rich protein content; 3) abnormal ultrastructural morphology of the mitochondria, with enlargement of the IMS space; and 4) accelerated time-dependent accumulation of multiple mtDNA deletions. Moreover, the Saccharomyces cerevisiae erv1(R182H) mutant strain reproduced the complex IV activity defect and exhibited genetic instability of the mtDNA and mitochondrial morphological defects. These findings shed light on the mechanisms of mitochondrial biogenesis, establish the role of GFER in the human DRS, and promote an understanding of the pathogenesis of a new mitochondrial disease.
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PMID:The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. 1940 22

Renal manifestations of mitochondrial cytopathies have been described, but nephrotic syndrome with respiratory-chain disorders have been described extremely rarely. We report a 9-month-old boy with a mitochondrial cytopathy preceded by a 2-month history of steroid-resistant nephrotic syndrome. Percutaneous renal biopsy revealed diffuse mesangial sclerosis, and mutational analysis was compatible with PLCE1 mutation. However, electron microscopic findings of renal tissue, sensorineural hearing loss, and other ocular and neurologic findings led us to suspect mitochondrial cytopathy. Muscle tissue analysis showed a deficiency of the respiratory chain complex IV. The clinical presentation of our patient is not typical for primary cytochrome oxidase (COX) deficiency but showed similarities with patients carrying AR mutations in COX10. This was the first case in the literature with both PLCE1 mutation and COX deficiency. We could not identify pathogenic mutations in the COX10 gene, suggesting that PLCE1 deficiency could be the cause of the secondary deficiency of COX. Another, more likely, possibility is that the mitochondriopathy phenotype is caused by another mutation homozygous by descent in a yet unidentified recessive gene.
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PMID:Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation. 2136 90

A deletion of one of the two copies of the 9-bp tandem repeat sequence (CCCCCTCTA), in the small non-coding/untranslated segment located between the cytochrome oxidase II and lysine tRNA genes of mitochondrial DNA (mtDNA), has previously been used as a polymorphic anthropological marker (MIC9D) for people of Africa and Asia, but it has been rarely reported in Europe. 32 Sicilian patients with syndromic hearing loss, negative for mutations in GJB2 and GJB6 genes, were tested for mtDNA known point mutations associated with syndromic or non-syndromic hearing loss by RFLP and/or direct sequencing. We identified the presence of the MIC9D in homoplasmy in lymphocytes and muscle of three subjects with sensorineural hearing loss and encephalomyopathy, two of these also presented moderate mental retardation. This deletion was absent in 300 Caucasian controls. Although further studies are warranted, our results suggest that the MIC9D polymorphism could have a susceptibility role in Caucasus, such as Sicily population.
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PMID:The 9-bp deletion in region V of mtDNA: a risk factor of hearing loss and encephalomyopathy in Caucasian populations? 2335 5

The overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been known to contribute to the pathogenesis of noise-induced hearing loss. In this study, we discovered that in BALB/c mice pretreatment with methylene blue (MB) for 4 consecutive days significantly protected against cochlear injury by intense broad-band noise for 3 h. It decreased both compound threshold shift and permanent threshold shift and, further, reduced outer hair cell death in the cochlea. MB also reduced ROS and RNS formation after noise exposure. Furthermore, it protected against rotenone- and antimycin A-induced cell death and also reversed ATP generation in the in vitro UB-OC1 cell system. Likewise, MB effectively attenuated the noise-induced impairment of complex IV activity in the cochlea. In addition, it increased the neurotrophin-3 (NT-3) level, which could affect the synaptic connections between hair cells and spiral ganglion neurons in the noise-exposed cochlea, and also promoted the conservation of both efferent and afferent nerve terminals on the outer and inner hair cells. These findings suggest that the amelioration of impaired mitochondrial electron transport and the potentiation of NT-3 expression by treatment with MB have a significant therapeutic value in preventing ROS-mediated sensorineural hearing loss.
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PMID:Attenuation of noise-induced hearing loss using methylene blue. 2476 57