Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0751651 (mitochondrial disease)
 1,844 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A systematic study of the effects of the synthetic glucocorticoid, methylprednisolone (MP), on respiration and energy coupling in tightly-coupled mitochondria isolated from rat tissues has been initiated. In intact rat skeletal muscle, liver and heart mitochondria, incubation, in vitro, with greater than or equal to 0.1 mM MP caused inhibition of the state 3 respiratory rates with succinate and NAD-linked substrates. In skeletal muscle and heart mitochondria, the oxidation of succinate was significantly more sensitive to MP than was that of the NAD-linked substrates. No effects were seen at low concentrations (less than 0.02 mM) of MP. In all three tissues, these data together with analysis of the partial reactions of the electron transport chain and steady-state kinetic analysis of cytochrome reduction indicated that in isolated mitochondria high concentrations of MP: (a) inhibit the oxidation of NAD-linked substrates at the level of the respiratory chain between the primary NADH dehydrogenase flavoprotein and coenzyme Q, most likely at the iron-sulfur centers or coenzyme Q-binding proteins of complex I; and (b) inhibit succinate oxidation in intact (but not disrupted) mitochondria, not by inhibiting electron transfer along the respiratory chain, but possibly at the level of succinate transport into the mitochondria. The results of these studies suggest that the therapeutic effects of MP in mitochondrial disease result from indirect effects rather than direct effects on the mitochondrial membrane. More importantly, the absence of an effect at low MP concentrations provides the baseline information needed for further studies to be carried out in vivo.
 ...
PMID:In vitro effects of glucocorticoid on mitochondrial energy metabolism. 204 73

An animal model is presented that provides constant and controllable conditions for approaching gradually, and within reasonable time, different stages of iron overload and, probably, an iron-induced mitochondrial disorder. Thirty-five rats were infused with ferric citrate, sodium citrate and saline at constant rates for 6-24 h. In the 200-3200 micrograms Fe h-1 loading range, the iron-incorporation capacity of the liver was not saturable and the fractional iron uptake by the liver remained at approximately 30% even at a loading rate of 3200 micrograms Fe h-1. Up to a loading rate of 200 micrograms Fe h-1, iron storage was not associated with toxic effects. Beyond this loading rate, however, the liver was no longer able to prevent a massive plasma iron increase on one side and hyperlactataemia on the other. These signs most probably represent hepatocellular decompensation with respect to a critical iron-storage rate. The product of plasma iron x exposition time was significantly correlated with increased plasma lactate levels (r = 0.89, P less than 0.005), whereas increased plasma iron levels per se were not. Hyperlactataemia was associated with hyperkalaemia and progressive cardiac conduction defects leading to cardiac arrest at lactate concentration of 9.1 +/- 4.3 mmol l-1. The hypothesis is discussed that toxicity in acute iron overload may entirely be due to hepatocellular (mitochondrial) damage, and not to multiple organ iron overload.
 ...
PMID:Hyperlactataemia, hyperkalemia and heart block in acute iron overload: the fatal role of the hepatic iron-incorporation rate in rats on ferric citrate infusions. 313 Feb 62

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive-gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S-dependent enzyme deficiencies in yeast. The deficiency of Fe-S-dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.
 ...
PMID:Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. 932 46

X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome.
 ...
PMID:Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). 1019 63

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V(max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V(max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.
 ...
PMID:Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. 1050 Jan 3

We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.
 ...
PMID:A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. 1115 34

Friedreich ataxia (FRDA) is an autosomal recessive degenerative disorder caused in the vast majority of cases by a GAA triplet expansion in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein which is severely reduced in FRDA patients. Loss of the homologue of frataxin in yeast is associated with mitochondrial iron overload, increased sensitivity to oxidative stress and profound deficit of oxidative phosphorylation. The demonstration that the human pathology of FRDA is also characterised by mitochondrial iron accumulation, deficit of respiratory chain complex activities and in vivo deficit of tissue energy metabolism establishes FRDA as a 'new' nuclear encoded mitochondrial disease.
 ...
PMID:Mitochondrial dysfunction in friedreich's ataxia. 1135 Nov 32

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.
 ...
PMID:Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives. 1206 11

Friedreich's ataxia (FA) is the most prevalent cerebellar ataxia in children and adults in Europe. FA is one of a growing number of diseases known to be caused by triplet-repeat expansions. The causative mutation is a GAA trinucleotide-repeat expansion in the first intron of the frataxin gene. The mitochondrial localisation of frataxin and decreased oxidation activity in vivo and in vitro show that FA is a mitochondrial disease. Frataxin is involved in iron metabolism and may protect mitochondria from oxidative damage. The understanding of the disease has only just begun and possible treatments are within reach. In this review I discuss the clinical knowledge of FA and recent developments that have helped to elucidate the pathogenesis of the disease and made the first therapeutic attempts possible.
 ...
PMID:Friedreich's ataxia: treatment within reach. 1284 98

Friedreich's ataxia, the most common hereditary ataxia, is caused by expansion of a GAA triplet located within the first intron of the frataxin gene on chromosome 9q13. There is a clear correlation between size of the expanded repeat and severity of the phenotype. Frataxin is a mitochondrial protein that plays a role in iron homeostasis. Deficiency of frataxin results in mitochondrial iron accumulation, defects in specific mitochondrial enzymes, enhanced sensitivity to oxidative stress, and eventually free-radical mediated cell death. Friedreich's ataxia is considered a nuclear encoded mitochondrial disease. This review discusses the major and rapid progress made in Friedreich's ataxia from gene mapping and identification of the gene to pathogenesis and encouraging therapeutic implications.
 ...
PMID:Friedreich's ataxia. 1287 93


1 2 3 4 Next >>