RESUMO
Mitochondrial diseases are usually severe and progressive conditions; however, there are rare forms that show remarkable spontaneous recoveries. Two homoplasmic mitochondrial tRNA mutations (m.14674T>C/G in mt-tRNA(Glu)) have been reported to cause severe infantile mitochondrial myopathy in the first months of life. If these patients survive the first year of life by extensive life-sustaining measures they usually recover and develop normally. Another mitochondrial disease due to deficiency of the 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) causes severe liver failure in infancy, but similar to the reversible mitochondrial myopathy, within the first year of life these infants may also recover completely. Partial recovery has been noted in some other rare forms of mitochondrial disease due to deficiency of mitochondrial tRNA synthetases and mitochondrial tRNA modifying enzymes. Here we summarize the clinical presentation of these unique reversible mitochondrial diseases and discuss potential molecular mechanisms behind the reversibility. Understanding these mechanisms may provide the key to treatments of potential broader relevance in mitochondrial disease, where for the majority of the patients no effective treatment is currently available.
Assuntos
Falência Hepática/genética , Doenças Mitocondriais/genética , Miopatias Mitocondriais/genética , RNA de Transferência/genética , Tionucleotídeos/deficiência , Tionucleotídeos/genética , Nucleotídeos de Uracila/deficiência , Nucleotídeos de Uracila/genética , Expressão Gênica , Humanos , Lactente , Recém-Nascido , MutaçãoRESUMO
Pyrimidine nucleosides in blood plasma of rats were identified by different procedures, including chemical peak shift methods, before their quantification by reversed-phase high-performance liquid chromatography. The concentrations of uridine, cytidine, and deoxycytidine were 1.0 +/- 0.2, 10.6 +/- 1.9, and 33.4 +/- 5.4 mumol/l, respectively. Six hours after the administration of D-galactosamine, the level of circulating cytidine was severely depressed to 25% of control values; uridine decreased to 54% while deoxycytidine remained unchanged. 24 h after the dose of the amino sugar, the levels of cytidine and uridine returned to control values in blood plasma. Total acid-soluble uridine, cytidine, guanosine, and adenosine was determined by reversed-phase HPLC after treatment of the neutralized acid-soluble supernatant of freeze-clamped rat livers with phosphodiesterase and alkaline phosphatase. Six hours after its administration, D-galactosamine induced a 2.2-fold and a 1.6-fold rise in total acid-soluble uridine and cytidine, respectively. Co-administration of N-(phosphonoacetyl)-L-aspartate, an inhibitor of de novo pyrimidine synthesis, suppressed the increase in total acid-soluble uridine observed after D-galactosamine alone, but was without effect on the enhancement of total cytidine. Three hours after D-galactosamine and 15 min after [2-14C] cytidine, there was a rapid fall of the labeled nucleoside in blood plasma to 49% of control animals accompanied by a 2.8-fold rise in the total radioactivity of rat liver homogenates. From these results it can be concluded that the hepatocellular rise in total acid-soluble cytidine after D-galactosamine, in contrast to the increase in total acid-soluble uridine, originates from the phosphorylation of blood plasma cytidine via the salvage pathway. The depletion of circulating cytidine in the presence of hepatocellular UTP deficiency points to the importance of the liver and the hepatic UTP level for the clearance of blood plasma cytidine.
Assuntos
Citidina/sangue , Galactosamina/farmacologia , Fígado/metabolismo , Nucleotídeos de Uracila/deficiência , Uridina Trifosfato/deficiência , Animais , Antimetabólitos/farmacologia , Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacologia , Cromatografia de Afinidade , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Fígado/efeitos dos fármacos , Nucleosídeos/metabolismo , Nucleotídeos/metabolismo , Ácido Fosfonoacéticos/análogos & derivados , Ácido Fosfonoacéticos/farmacologia , Ratos , Ratos Endogâmicos , SolubilidadeRESUMO
In the rat, 2 h after intraventricular application of 10 mumoles D-galactosamine as well as 10 and 20 mumoles uridine, opposite effects on brain content of UDP-glucose and uracil nucleotides were observed. While D-galactosamine caused a strong decrease in content of uridine phosphates, the brain content of the latter substances was markedly increased after uridine application. Furthermore, 20 mumoles uridine applied 10 min prior to D-galactosamine administration prevented the D-galactosamine-induced drop in brain uridine phosphates. The results are discussed in the light of behavioural findings in which D-galactosamine-induced impairment of retention performance of an acquired behaviour could be abolished by uridine pretreatment.
Assuntos
Encéfalo/efeitos dos fármacos , Galactosamina/toxicidade , Nucleotídeos de Uracila/deficiência , Uridina/farmacologia , Animais , Encéfalo/metabolismo , Química Encefálica , Galactosamina/administração & dosagem , Injeções Intraventriculares , Masculino , Ratos , Ratos EndogâmicosAssuntos
Citidina Trifosfato/metabolismo , Nucleotídeos de Citosina/metabolismo , Nucleotídeos de Uracila/deficiência , Uridina Trifosfato/deficiência , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Técnicas In Vitro , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Ratos , Fatores de Tempo , Uridina Trifosfato/metabolismoRESUMO
Five galactosemic and 5 normal children received an oral load of galactose under standardized conditions. The maximal blood galactose level after 1.5 hours was 12.6 +/- 2.0 (S.D.) mmol/l in individuals with a deficiency of uridylyl transferase (EC2.7.7.12) as compared to 5.8 +/- 1.2 (S.D.) mmol/l in the controls. The concentration of serum urate in galactosemics increased to 155% of the fasting level (P less than 0.005); no rise was detectable in the controls. The elimination of urate with the urine was augmented by the same amount in both groups. Our studies provide evidence for an increased catabolism of hepatic nucleotides. This may lead to a deficiency of nucleotides which is proposed as a cause of galactosemic liver injury.