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At least 181 records · Page 10Linked to original sources
PubMed1996

Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts.

We report on 2 children, brother and sister, who presented with cardiomyopathy and muscular hypotonia at the age of B months. They both excreted significant amounts of 3-hydroxy-3-methylglutaric acid (3-HMG) and 3-methylglutaconic acid (3-MGC) but no 3-methylglutaric acid (3-MG). Enzyme analysis in fibroblasts revealed normal activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase and of 3-methylglutaconyl hydratase and other enzymes of 3-HMG metabolism. Loading tests with leucine did not affect the excretion of 3-HMG and 3-MGC. The girl died as a result of her cardiomyopathy, while the boy recovered and was treated with cardiac supportive therapy. He showed a steady improvement during his clinical course with biochemical normalization of the urinary excretion of 3-HMG, concomitant with marked improvement in the hypertrophic cardiomyopathy. In cultured fibroblasts from both patients a reduced activity of complex II/III of the respiratory chain was measured which may be the cause of this new type of 3-HMG uria. Analysis of mitochondrial DNA heart muscle, liver and fibroblast culture of the patient did not reveal any major mitochondrial DNA rearrangements (deletion, duplication) or any point mutation that had been described in association with mitochondrial cardiomyopathy.

Cardiomyopathy, Dilated↗
PubMed2005

Impact of mitochondria and NADPH oxidases on acute and sustained hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.

Defects of complex I of the mitochondrial respiratory chain are important causes of neurological disease. We report studies that demonstrate a severe deficiency of complex I activity with less severe abnormalities of complexes III and IV (less than 5, 63, and 30% of control values, respectively) in a skeletal muscle mitochondrial fraction from a 22-yr-old female with weakness, lactic acidemia, and the deposition of intramuscular neutral lipid. The observation that lipid accumulates in this and other patients with complex I deficiency suggests impaired mitochondrial fatty acid oxidation. To investigate this mechanism we have shown impaired flux through beta-oxidation [( U-14C]hexadecanoate oxidation was 66% of control rate) and accumulation of specific acyl-CoA ester intermediates. The changes in fatty acid metabolism in complex I deficiency are secondary to the reduced state within the mitochondrial matrix with low NAD+/NADH ratios.

Adult↗
PubMed2002

Infantile leukoencephalopathy owing to mitochondrial enzyme dysfunction.

Mitochondrial disease is classically associated with deep gray-matter lesions. When white matter is involved, the lesions are typically subcortical and overshadowed by more significant disease in the gray matter. We report six infants in five families who developed neurodegenerative diseases characterized primarily by abnormalities in deep white-matter structures such as the periventricular region, internal capsule, and corpus callosum. Five patients had impairments of mitochondrial enzymes, including a pre-electron transport chain defect and defects in respiratory chain complexes I, III, and IV (cytochrome-c oxidase). One patient, the sibling of one of the others, was diagnosed clinically with complex III deficiency. These six patients, along with others in the literature, appear to represent a distinct syndrome of mitochondrial infantile leukoencephalopathy. Our observations suggest that infants with leukoencephalopathies, especially leukodystrophies, who do not have one of the more common causes of white-matter disease should be evaluated for mitochondrial dysfunction.

Corpus Callosum↗
PubMed2002

Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.

A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.

Adolescent↗
PubMed2003

Ischemic pre-conditioning preserves brain mitochondrial functions during the middle cerebral artery occlusion in rat.

It is well known that a brief period of ischemia increases tolerance to a subsequent severe ischemic episode. In the present study, bilateral carotid arteries occlusion (BCAO) was applied as pre-conditioning to testify whether this kind of ischemia could preserve the function of mitochondria with the impairment induced by middle cerebral artery occlusion (MCAO) in brain. The activities of respiratory enzyme complex I to IV, mitochondria swelling, membrane potential, and membrane fluidity were investigated. The results showed that the percentage of infarct area decreased greatly due to the ischemic pre-conditioning (IP) revealing the preventive effect of IP on infarct size. The activities of respiratory enzyme complex III, IV were effectively preserved (p < 0.05, p < 0.05) compared with MCAO group through ischemic pre-conditioning. Mitochondrial swelling and membrane fluidity were protected by IP, and also an increased trend was found in membrane potential, which indicated that the integrity of mitochondrial membrane was maintained. It suggested that the function of mitochondrial energy metabolism in brain ischemia was effectively protected by this kind of pre-conditioning.

Animals↗
PubMed2002

Ca(2+) and Na(+) dependence of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons.

Glutaryl-CoA dehydrogenase deficiency (also known as glutaric aciduria type I) is an autosomal, recessively inherited neurometabolic disorder with a distinct neuropathology characterized by acute encephalopathy during a vulnerable period of brain development. Neuronal damage in this disease was demonstrated to involve N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the endogenously accumulating metabolite 3-hydroxyglutarate (3-OH-GA). However, it remained unclear whether NMDA receptors are directly or indirectly activated and whether 3-OH-GA disturbs the intracellular Ca(2+) homeostasis. Here we report that 3-OH-GA activated recombinant NMDA receptors (e.g. NR1/NR2A) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (e.g. GluR-A/GluR-B) in HEK293 cells. Fluorescence microscopy using fura-2 as Ca(2+) indicator revealed that 3-OH-GA increased intracellular Ca(2+) concentrations in the presence of extracellular Ca(2+) in cultured chick neurons. Similar to glutamate-induced cell damage, 3-OH-GA neurotoxicity was modulated by extracellular Na(+). The large cation N-methyl-D-glucamine, which does not permeate NMDA receptor channels, enhanced 3-OH-GA-induced Ca(2+) increase and cell damage. In contrast, 3-OH-GA-induced neurotoxicity was reduced after replacement of Na(+) by Li(+), which permeates NMDA channels but does not affect the Na(+)/Ca(2+) exchanger in the plasma membrane. Spectrophotometric analysis of respiratory chain complexes I-V in submitochondrial particles from bovine heart revealed only a weak inhibition of 3-OH-GA on complex V at the highest concentration tested (10 mM). In conclusion, the present study revealed that NMDA receptor activation and subsequent disturbance of Ca(2+) homeostasis contribute to 3-OH-GA-induced cell damage.

Adenosine Triphosphatases↗
PubMed2005

Carbenoxolone induces oxidative stress in liver mitochondria, which is responsible for transition pore opening.

Carbenoxolone (Cbx), a derivative of glycyrrhetinic acid, which has been found to affect mineralocorticoid and glucocorticoid receptors, induces swelling and membrane potential collapse when added to Ca(2+)-loaded liver mitochondria at 10 microM concentrations. These effects are strictly correlated with hydrogen peroxide generation, increase in oxygen uptake, and sulfhydryl and pyridine nucleotide oxidation. Cyclosporin A, bongkrekic acid, and N-ethylmaleimide completely abolish all the above-described effects, suggesting that Cbx can be considered an inducer of mitochondrial permeability transition by means of oxidative stress. Cbx can also trigger the apoptotic pathway because the above events are also correlated with the loss of cytochrome c. These effects are probably related to the conjugated carbonyl oxygen in C-11, which produces reactive oxygen species by interacting with the mitochondrial respiratory chain, mainly at the level of complex I but, most likely, also with complex III. The oxidative stress induced by Cbx, which is responsible for pore opening, excludes that this is related to a genomic effect of the compound.

Animals↗
PubMed1995

Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism.

Previous studies have demonstrated impaired complex I activity in platelets from Parkinson's disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopa/levodopa for 1 month, and after receiving carbidopa/levodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications.

Adult↗
PubMed1996

Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from untreated Parkinson's disease patients. Grupo-Centro de Trastornos del Movimiento.

We studied respiratory-chain enzyme activities in lymphocyte mitochondria from 36 untreated Parkinson's disease (PD) patients and in 30 age- and sex-matched healthy controls. The respiratory-chain enzyme activities did not differ significantly between patients and controls. Moreover, no patient showed respiratory-chain enzyme levels below normal range. Values for activities of complexes in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinson's Disease Rating scales, or Hoehn and Yahr staging. These results suggest that the presence of defects of respiratory-chain complexes could depend on methodologic aspects, and that determinations of respiratory-chain enzymes in cell homogenates are not generally appropriate for evaluating abnormal mitochondrial dysfunction, especially when the amount of the specific enzyme is relatively low, as is the case of blood cells. In addition, the method of measuring complex I activity is critical for evaluating the results. In conclusion, our finding of normal mitochondrial function in lymphocyte mitochondria suggests that this tissue cannot be used to develop a diagnostic test for PD.

Citrate (si)-Synthase↗