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)

One cause of congenital lactic acidosis is a mutation in the E1 alpha-subunit of the pyruvate dehydrogenase multienzyme complex. Little is known about the consequences of these mutations at the enzymatic level. Here we study the A199T mutation by expressing the protein in Escherichia coli. The specific activity is 25% of normal and the K(m) for pyruvate is elevated by 10-fold. Inhibitors of lactate dehydrogenase might be a useful therapy for patients with such mutations.
Mol Genet Metab 2001 Mar
PMID:Congenital lactic acidosis: evaluation of the properties of the a199t natural variant of human pyruvate dehydrogenase e1alpha by in vitro mutation. 1124 35

A deficiency of pyruvate dehydrogenase complex (PDC) in humans results in lactic acidosis and neurological dysfunction that frequently results in death during infancy. Using gene targeting technology, a silent mutation was introduced into the murine X-linked Pdha1 gene that encodes the alpha subunit of the pyruvate dehydrogenase or E1 component of the complex. Two loxP sequences were introduced into intronic sequences flanking exon 8 to generate the Pdha1(flox8) allele. In vitro studies in embryonic stem cells demonstrated that deletion of exon 8 ablated PDC activity. Homozygous Pdha1(flox8) females were bred with male mice carrying a wild-type Pdha1 allele and a transgene that ubiquitously expresses the Cre recombinase to produce progeny with a deletion in exon 8, Pdha1(Deltaex8). The majority of progeny were found to be mosaic with the presence of both the flox and deleted alleles, and there were no apparent phenotypic effects associated with the null allele. The mosaic mice were interbred to increase the degree of mosaicism for the Pdha1(Deltaex8) allele in the subsequent generation, resulting in a significantly smaller litter size (54% reduction). Embryos carrying predominantly the Pdha1(Deltaex8) allele were found to be globally delayed in development by 9.5 days postcoitus, with resorption occurring over the following several days. These findings demonstrate an essential role for oxidative metabolism of glucose during the early postimplantation period of prenatal development.
Mol Genet Metab 2001 Nov
PMID:Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. 1170 58

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q33-37. The basic defect of the disease remains unknown.
Pediatr Pathol Mol Med
PMID:Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE). 1194 35

Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.
Mol Genet Metab
PMID:Pyruvate carboxylase deficiency--insights from liver transplantation. 1235 42

GRACILE syndrome (Fellman syndrome, MIM 603358), an autosomal recessive metabolic disorder of the Finnish disease heritage, has been diagnosed in 25 infants of 18 families. The incidence is at least 1/47,000 in Finland. The main findings are fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload (liver hemosiderosis, hyperferritinemia, hypotransferrinemia, increased transferrin iron saturation, and free plasma iron), profound lactic acidosis, and early death. The pathophysiology of the metabolic disturbance is unsolved. No significant deficiency of complex III activity of respiratory chain has been found, although we recently showed that the underlying genetic cause is a missense mutation (S78G) in the BCS1L gene and other mutations in that gene have been associated with complex III deficiency. BCS1L encodes a mitochondrial protein, acting as a chaperone in the assembly of complex III. Iron accumulation in liver, a typical feature being less abundant with increasing age, might be a primary abnormality or a secondary phenomenon due to liver dysfunction. In order to decrease the iron overload, three infants have been repeatedly treated with apotransferrin followed by exchange transfusion. Improvement in iron biochemistry occurred, but no clear beneficial effect on the clinical condition was found. Further studies will elucidate the role of iron in the pathophysiology of the disease.
Blood Cells Mol Dis
PMID:The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. 1254 34

Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1; Slc22a1) and, using Oct1(-/-) mice, that mouse Oct1 is responsible for the hepatic uptake of a biguanide, metformin. In the present study, we investigated whether the liver is the key organ for the lactic acidosis. When mice were given metformin, the blood lactate concentration significantly increased in the wild-type mice, whereas only a slight increase was observed in Oct1(-/-) mice. The plasma concentration of metformin exhibited similar time profiles between the wild-type and Oct1(-/-) mice, suggesting that the liver is the key organ responsible for the lactic acidosis. Furthermore, the extent of the increase in blood lactate caused by three different biguanides (metformin, buformin, and phenformin) was compared with the abilities to reduce oxygen consumption in isolated rat hepatocytes. When rats were given each of these biguanides, the lactate concentration increased significantly. This effect was dose-dependent, and the EC(50) values of metformin, buformin, and phenformin were 734, 119, and 4.97 microM, respectively. All of these biguanides reduced the oxygen consumption by isolated rat hepatocytes in a concentration-dependent manner. When the concentration required to reduce the oxygen consumption to 75% of the control value (from 0.40 to 0.29 micromol/min/mg protein) was compared with the EC(50) value obtained in vivo, a clear correlation was observed among the three biguanides, suggesting that oxygen consumption in isolated rat hepatocytes can be used as an index of the incidence of lactic acidosis.
Mol Pharmacol 2003 Apr
PMID:Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. 1264 85

Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.
Hum Mol Genet 2004 Feb 01
PMID:Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis. 1466 56

Lactic acidosis is a rare but potentially life-threatening and poorly understood sequelae among HIV-infected patients on highly active antiretroviral therapy (HAART). Mitochondrial DNA depletion and inhibition of respiratory complexes have been hypothesized to be involved in HAART-associated lactic acidosis. Although mitochondrial toxicity and increased plasma lactates are associated with long-term exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI), reports of lactic acidosis are now emerging among HIV-infected patients exposed to combination therapy that includes not only NRTI but also protease inhibitors (PI). We therefore investigated the effects of clinically relevant NRTI and PI combinations on mitochondrial membrane potential, uncoupling of mitochondrial respiration from oxidative phosphorylation and lactic acid production. Our study demonstrated that treatment of HepG2 cells with a combination of nucleoside analogues and PI, decreased mitochondrial membrane potential (delta psi m) within 24 hr, followed by increased lactic acid production after 9 days of treatment. However, loss of delta psi m and increased lactates were not associated with mitochondrial uncoupling or ATP production. Our findings suggested that not only NRTI but also PI are capable of increasing lactic acid production in vitro, and probably involve early biochemical changes in mitochondrial function such as loss of mitochondrial membrane potential.
Cell Mol Biol (Noisy-le-grand) 2003 Dec
PMID:Highly active antiretroviral therapy (HAART)-associated lactic acidosis: in vitro effects of combination of nucleoside analogues and protease inhibitors on mitochondrial function and lactic acid production. 1498 88

Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of these mutations impair one or more steps of tRNA maturation and protein biosynthesis including 5'-end-processing, post-transcriptional base modification, structural stability, aminoacylation, and formation of tRNA-ribosomal complexes. tRNALeu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90 disease-associated mutations described to date. Here, the pathogenesis-associated base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA were tested for their effects on endonucleolytic 3'-end processing and CCA addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a less efficient substrate for CCA addition. These results support the view that pathogenesis may be elicited through cumulative effects of tRNA mutations: a mutation can impede several pre-tRNA processing steps, with each such reduction contributing to the overall impairment of tRNA function.
J Mol Biol 2004 Mar 26
PMID:A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition. 1501 75

Oncocytic changes seen in hepatocytes in patients receiving highly active antiretroviral therapy (HAART) are a result of mitochondrial damage. This is the first report that provides the electron microscopy illustration of mitochondrial proliferation as a result of the HAART drug Stavudine (Zerit) hepatotoxicity. The drug's effect on mitochondrial DNA replication leads to depleted mitochondrial-encoded proteins and configurational defects of the mitochondrial inner membrane leading to reduced and abnormal cristae, which house the electron transport chain and elementary bodies. This results in a decrease in the NAD/NADH ratio and reduces oxidative phosphorylation. The shift in the NAD/NADH ratio decreases the rate of fatty acid beta oxidation and oxidation of pyruvate by the Krebs cycle. Decreased oxidation of pyruvate drives it into an alternative pathway to form lactate leading to lactic acidosis. This mitochondrial dysfunction results in a compensatory increase in mitochondrial biogenesis, which results in oncocytic changes of the hepatocytes.
Exp Mol Pathol 2004 Dec
PMID:Drug-induced increased mitochondrial biogenesis in a liver biopsy. 1550 36


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