Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA have been implicated in a wide range of degenerative diseases. MtDNA base substitution and rearrangement mutations can cause myopathy, cardiomyopathy, ophthalmological defects, growth retardation, movement disorders, dementias, and diabetes. nDNA mutations can affect mtDNA replication and transcription, increase mtDNA mutations through defects in the adenine nucleotide translocator isoform 1 (ANT1), or cause Leigh's syndrome, as a result of defects in oxidative phosphorylation (OXPHOS) structural genes. Mouse models of mtDNA base substitution mutations have been created by introducing the mtDNA 16S rRNA chloramphenicol (CAP)-resistance mutation into the mouse female germline. This resulted in ophthalmological defects in chimeras and perinatal lethality resulting from myopathy and cardiomyopathy in mutant animals. Mouse models of mtDNA rearrangements have resulted in animals with myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the mouse nDNA mitochondrial transcription factor (Tfam) gene in the heart caused neonatal lethal cardiomyopathy, whereas its inactivation in the pancreatic beta-cells caused diabetes. Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. This suggests that multiple mtDNA deletion syndrome can be caused by increased ROS damage. The inactivation of the uncoupler protein genes (Ucp) 1-3 resulted in alterations in delta mu H+ and increased ROS production. Inactivation of the Ucp2 gene, which is expressed in the pancreatic beta-cells, resulted in increased islet ATP, increased serum insulin levels, and suppression of the diabetes of the ob/ob mouse genotype. Transgenic mice with altered beta-cell ATP-sensitive K+ channels (KATP) also developed diabetes. Mutational inactivation of the mitochondrial antioxidant genes for glutathione peroxidase (GPx1) and Mn superoxide dismutase (Sod2) caused reduced energy production and neonatal lethal dilated cardiomyopathy, respectively, the later being ameliorated by treatment with MnSOD mimics. Partial Sod2 deficiency (+/-) resulted in mice with increased mitochondrial damage during aging, and treatment of C. elegans with catalytic antioxidant drugs can extend their life-span. Mice deficient in cytochrome-c died early in embryogenesis, but cells derived from these embryos had a complete deficiency in mitochondrial apoptosis. Mice lacking the proapoptotic Bax and Bak genes were not able to release cytochrome-c from the mitochondrion and were blocked in apoptosis. Mice lacking Apaf1, Cas9, and Cas3 did release mitochondrial cytochrome-c and were blocked in the downstream steps of apoptosis. These animal studies confirm that alterations in mitochondrial energy generation, ROS production, and apoptosis can all contribute to the pathophysiology of mitochondrial disease.
Methods Mol Biol 2002
PMID:Animal models for mitochondrial disease. 1201 5

Mutations in the E3-binding protein component of pyruvate dehydrogenase complex have been demonstrated in a few cases of Leigh syndrome. We report that two mutations previously detected in the E3-binding protein cDNA are the consequence of splice-site mutations. Both involved a single base substitution in the conserved dinucleotides of splice junctions, one leading to skipping of an exon and the other, to activation of a cryptic site. Our findings add to the understanding of molecular basis of E3-binding protein deficiency and indicate yet again the high frequency of splicing mutations in this gene.
Mol Genet Metab 2002 Aug
PMID:Pyruvate dehydrogenase deficiency as a result of splice-site mutations in the PDX1 gene. 1220 41

We previously reported that histamine H(3) receptors (H(3)Rs) are present in cardiac sympathetic nerve endings (cSNE) of animals and humans, where they attenuate norepinephrine (NE) release in normal and hyperadrenergic states, such as myocardial ischemia. The recent creation of a transgenic line of mice lacking H(3)R provided us with the opportunity to assess the relevance of H(3)R in the ischemic heart. We isolated SNE from hearts of wild-type (H(3)R(+/+)) and knockout (H(3)R(-/-)) mice and found that basal NE release from H(3)R(-/-) cSNE was approximately 60% greater than that from H(3)R(+/+) cSNE. NE exocytosis evoked by K(+)-induced depolarization of cSNE from H(3)R(+/+) mice was attenuated by activation of either H(3)R or adenosine A(1) receptors (A(1)R). In contrast, NE release from cSNE of H(3)R(-/-) was unaffected by H(3)R agonists, but it was still attenuated by A(1)R activation. When isolated mouse hearts were subjected to ischemia for 20 min, NE overflow into the coronaries was 2-fold greater in the H(3)R(-/-) hearts than in those from H(3)R(+/+) mice. Furthermore, whereas stimulation of H(3)R or A(1)R reduced ischemic NE overflow from H(3)R(+/+) hearts by 50%, only A(1)R, but not H(3)R activation, reduced NE release in H(3)R(-/-). Our data demonstrate that NE release from cSNE can be modulated by various heteroinhibitory receptors (e.g., H(3)R and A(1)R) and that H(3)Rs are particularly important in modulating NE release in myocardial ischemia. Inasmuch as excessive NE release is clinically recognized as a major cause of arrhythmic cardiac dysfunction, our findings reveal a significant cardioprotective role of H(3)R on cSNE.
Mol Pharmacol 2003 Feb
PMID:Norepinephrine release from the ischemic heart is greatly enhanced in mice lacking histamine H3 receptors. 1252 9

We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting approximately 90% of the Surf1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency in vivo, and evaluate the efficacy of treatment.
Hum Mol Genet 2003 Feb 15
PMID:Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. 1256 87

Deficiencies in the activity of cytochrome c oxidase (COX) are an important cause of autosomal recessive respiratory chain disorders. Patients with isolated COX deficiency are clinically and genetically heterogeneous, and mutations in several different assembly factors have been found to cause specific clinical phenotypes. Two of the most common clinical presentations, Leigh Syndrome and hypertrophic cardiomyopathy, have so far only been associated with mutations in SURF1 or SCO2 and COX15, respectively. Here we show that expression of COX10 from a retroviral vector complements the COX deficiency in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy. A partial rescue was also obtained following microcell-mediated transfer of mouse chromosomes into patient fibroblasts. COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2. Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme. Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues. A topological model places these residues in regions of the protein shown to have important catalytic functions by mutation analysis of a prokaryotic ortholog. Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy. This study shows that mutations in this gene can cause nearly the full range of clinical phenotypes associated with early onset isolated COX deficiency.
Hum Mol Genet 2003 Oct 15
PMID:Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. 1292 84

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.
Mol Genet Metab 2003 Aug
PMID:Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency. 1294 44

A T8993G point mutation in the mtDNA results in a Leu156Arg substitution in the MTATP6 subunit of the mitochondrial F1F0-ATPase. The T8993G mutation causes impaired oxidative phosphorylation (OXPHOS) in two mitochondrial disorders, NARP (neuropathy, ataxia and retinitis pigmentosa) and MILS (maternally inherited Leigh's syndrome). It has been reported, in some studies, that the T8993G mutation results in loss of assembled F1F0-ATPase. Others reported that the mutation causes impairment of proton flow through F0. In addition, it was shown that fibroblasts from NARP subjects have a tendency to undergo apoptotic cell death, perhaps as a result of increased free radical production. Here, we show that the T8993G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. We suggest that free radical-mediated inhibition of OXPHOS contributes to the loss of ATP synthesis. Importantly, we show that antioxidants restore respiration and partially rescue ATP synthesis in cells harboring the T8993G mutation. Our results indicate that free radicals might play an important role in the pathogenesis of NARP/MILS and that this can be prevented by antioxidants. The effectiveness of antioxidant agents in cultured NARP/MILS cells suggests that they might have a potential beneficial role in the treatment of patients with NARP.
Hum Mol Genet 2004 Apr 15
PMID:The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. 1499 33

White matter involvement is recently being realized as a common finding in mitochondrial disorders. It is considered an inherent part of the classical mitochondrial syndromes which are usually associated with alterations in the mitochondrial DNA such as: Leigh disease, Kearns-Sayre syndrome, mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes, mitochondrial neuro-gastro-intestinal encephalomyopathy and Leber's hereditary optic neuropathy. White matter involvement is also described in mitochondrial disorders due to mutations in the nuclear DNA which are transmitted in an autosomal pattern. MRI findings suggestive of a mitochondrial disease are: small cyst-like lesions in abnormal white matter, involvement of both cerebral and cerebellar white matter, and a combination of a leukoencephalopathy with bilateral basal ganglia lesions. The clinical manifestations may be disproportionate to the extent of white matter involvement. Other organs may frequently be involved. The onset is often in infancy with a neurodegenerative course. The finding of a leukoencephalopathy in a patient with a complex neurologic picture and multisystem involvement should prompt a thorough mitochondrial evaluation.
Mol Genet Metab 2005 Feb
PMID:White matter involvement in mitochondrial diseases. 1567 Jul 18

A family presented with three affected children with Leigh syndrome, a progressive neurodegenerative disorder. Analysis of the OXPHOS complexes in muscle of two affected patients showed an increase in activity of pyruvate dehydrogenase and a decrease of complex V activity. Mutation analysis revealed the T9176C mutation in the mtATPase 6 gene (OMIM 516060) and the mutation load was above 90% in the patients. Unaffected maternal relatives were tested for carrier-ship and one of them, with a mutation load of 55% in blood, was pregnant with her first child. The possibility of prenatal diagnosis was evaluated. The main problem was the lack of data on genotype-phenotype associations for the T9176C mutation and on variation of the mutation percentage in tissues and in time. Therefore, multiple tissues of affected and unaffected carriers were analysed. Eventually, prenatal diagnosis was offered with understanding by the couple that there could be considerable uncertainty in the interpretation of the results. Prenatal diagnosis was carried out twice on cultured and uncultured chorion villi and amniotic fluid cells. The result was a mutation percentage just below the assumed threshold of expression (90%). The couple decided to continue the pregnancy and an apparently healthy child was born with an as yet unclear prognosis. This is the first prenatal diagnosis for a carrier of the T9176C mutation. Prenatal diagnosis for this mutation is technically reliable, but the prognostic predictions are not straightforward.
Mol Hum Reprod 2005 Mar
PMID:Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. 1570 56

Pyruvate dehydrogenase (PDH) complex deficiency is a major cause of lactic acidosis and Leigh's encephalomyelopathies in infancy and childhood, resulting in early death in the majority of patients. Most of the molecular defects have been localized in the coding regions of the E1alpha PDH gene. Recently, we identified a novel mutation of the E1alpha PDH gene in a patient with an encephalopathy and lactic acidosis. This mutation, located downstream of exon 7, activates a cryptic splice donor and leads to the retention of intronic sequences. Here, we demonstrate that the mutation results in an increased binding of the SR protein SC35. Consistently, ectopic overexpression of this splicing factor enhanced the use of the cryptic splice site, whereas small interfering RNA-mediated reduction of the SC35 protein levels in primary fibroblasts from the patient resulted in the almost complete disappearance of the aberrantly spliced E1alpha PDH mRNA. Our findings open the exciting prospect for a novel therapy of an inherited disease by altering the level of a specific splicing factor.
Mol Cell Biol 2005 Apr
PMID:The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. 1579 12


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