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Biomedical subjects

J M Cooper

Publications and source records attributed to J M Cooper.

At least 109 records · Page 6Linked to original sources
PubMed1994

Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases.

Incubation of rat skeletal muscle mitochondria with the nitric oxide generator, S-nitrosoglutathione (GSNO) reversibly inhibited oxygen utilisation with all substrates tested. The visible absorption spectra of the inhibited mitochondria showed that cytochromes c+c1, b and a+a3 were reduced, indicating a block at the distal end of the respiratory chain. Analysis of the respiratory chain enzyme activities in the presence of GSNO localised the site of inhibition of cytochrome c oxidase alone. These results indicate that nitric oxide is capable of rapidly and reversibly inhibiting the mitochondrial respiratory chain and may be implicated in the cytotoxic effects of nitric oxide in the CNS and other tissues.

Animals↗
PubMed1994

Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease.

Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone-sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Complex I, iron, and ferritin in Parkinson's disease substantia nigra.

Elevated iron levels, enhanced oxidative damage, and complex I deficiency have been identified in the substantia nigra of Parkinson's disease patients. To understand the interrelationship of these abnormalities, we analyzed iron levels, ferritin levels, and complex I activity in the substantia nigra of patients with Parkinson's disease. Total iron levels were increased significantly, ferritin levels were unchanged, and complex I activities were decreased significantly in the substantia nigra samples. The failure of ferritin levels to increase with elevated iron concentrations suggests that the amount of reactive iron may increase in the substantia nigra of Parkinson's disease patients. There was no correlation between the iron levels and complex I activity or the iron-ferritin ratio and complex I activity in the substantia nigra samples.

Aged↗
PubMed1994

Platelet mitochondrial function in Leber's hereditary optic neuropathy.

We report the effect of the 11,778 and 3460 base pair mitochondrial DNA mutations, found in Leber's hereditary optic neuropathy (LHON), on platelet mitochondrial respiratory chain enzyme activity. We measured respiratory chain enzyme activities in platelets from 4 patients with the 3460 mutation, 17 patients with the 11,778 mutation and compared them with those of 41 healthy age-matched controls. We observed a 67% (P < 0.001) reduction in the mean NADH CoQ1 reductase (complex I) activity of the 3460 group compared to the control group. It has been shown previously that platelet mitochondrial biochemistry is affected by cigarette smoking. A significant reduction (25%, P < 0.03) in the mean complex I activity of the 11,778 group was only observed when the non-smokers within that group were compared to the non-smoking controls. The effect of smoking observed in this study may explain why previous workers have not observed a decrease in complex I activity associated with the 11,778 mutation. There was no significant change in the activity of complexes II/III or IV with either of these mutations. There was a significant increase (26%, P < 0.008) in citrate synthase (CS) activity with the non-smoking 11,778 group compared to the non-smoking control group, rising to 40% (P < 0.002) in those with this mutation who smoked. This reflects an increase in mitochondrial mass with the 11,778 mutation. This effect was not observed with the 3460 mutation even though the complex deficiency was much more severe.

Blood Platelets↗
PubMed1994

Mitochondrial DNA mutation underlying Leigh's syndrome: clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy.

An 18-year-old male patient presented with clinical and radiological evidence of Leigh's syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy. Biochemical studies showed reduced activity of complexes I and IV of the respiratory chain in mitochondria from heart, liver and kidney. The mutation of mitochondrial DNA (mtDNA) at position 8344, commonly associated with the syndrome of myoclonic epilepsy and ragged red fibres, was detected in the patient's blood and was present in muscle, brain, liver, heart, and kidney in uniformly high amounts. It is clear that LS is genetically heterogeneous and represents one of the most severe phenotypes of a number of different mtDNA defects.

Adolescent↗
PubMed1994

A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson's disease.

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.

Adolescent↗
PubMed1994

Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson's disease.

The mode of cell death in Parkinson's disease (PD) substantia nigra is uncertain. However, evidence is accumulating that certain of the biochemical abnormalities present in PD nigra at the time of death may precipitate apoptosis. We have investigated the mode of death induced by complex I inhibition of dopaminergic cell cultures, and our results suggest that both 1-methyl-4-phenylpyridinium and rotenone cause apoptosis at low concentrations and necrosis at high concentrations. This dose-dependent shift in the mode of cell death induced by these mitochondrial toxins may have important implications for the mechanisms of neuronal cell death in PD.

1-Methyl-4-phenylpyridinium↗
PubMed1994

Migration and market wage risk.

The author presents an approach to the analysis of labor migration that incorporates the role of market wage variability as a source of information in individual migration decisions. "The focus...is on quantifying the effects of the origin market acting through amenities and the share of market-specific wage variability as it affects forecasts of alternative wages and forecast precision. A subsample of employed males...from the [U.S.] National Longitudinal Survey of Youth (NLS) age 16 to 22 years is used for estimation. The empirical results are consistent with the theoretically predicted relationship between migration propensities and regional differences in the information content of wages. In addition, the results provide evidence that risk aversion deters migration given uncertainty, measured by forecast precision, about alternative market wage levels."

Americas↗
PubMed1993

Iron induced oxidative stress and mitochondrial dysfunction: relevance to Parkinson's disease.

Inactivation of the mitochondrial respiratory chain in response to iron-induced oxidative stress has been studied in cultured cells. Iron loading resulted in malonaldehyde production, decreased levels of glutathione and reduced specific activities of both complexes I and IV of the respiratory chain. These results are discussed with respect to idiopathic Parkinson's disease, which is associated with increased iron levels and a specific decrease in complex I activity in the substantia nigra.

Animals↗
PubMed1993

Free radicals and mitochondrial dysfunction in Parkinson's disease.

The precise relationship of the complex I deficiency in PD to the dopaminergic cell death and aetiology of this disorder is as yet unknown. However, evidence is accruing that this mitochondrial defect may play a central role in the cascade of events that terminates in nigral neuronal loss. Further work needs to be carried out to determine the molecular mechanisms that underlie the complex I deficiency as these may provide important indicators to the ultimate cause of PD. This may involve a genetic abnormality of complex I that may convey a susceptibility to developing PD. Alternatively, exogenous or endogenous toxic agents may target nigral complex I along pathways similar to those recognized for MPTP. A combination of a genetic predisposition in addition to an environmental precipitant has gained substantial support as an explanation for the cause of PD.

Cell Death↗
PubMed1993

A new point mutation associated with mitochondrial encephalomyopathy.

Point mutations in the mitochondrial gene tRNA leucine(UUR) have been associated with maternally inherited mitochondrial myopathies including the MELAS syndrome (Mitochondrial Myopathy Encephalopathy Lactic acidosis and Stroke-like episodes). We describe a further mutation in tRNA leucine(UUR) in a patient with mitochondrial encephalomyopathy, pigmentary retinopathy, dementia, hypoparathyroidism and diabetes mellitus. The mutation was heteroplasmic in the proband's blood (30%) and muscle (76%); it was present at high levels in the proband's affected mother (50% in muscle), and at low levels (< 10%) in blood, muscle and fibroblasts of an unaffected sister. The mutation was not found in 121 normal controls or 35 other patients with mitochondrial disorders. The mutation is at a highly conserved position in the tRNA molecule, close to the 3,243 mutation which is associated with more than 80% of MELAS cases. Further more, both mutations lie within a possible transcriptional control region. This finding adds further support to the evidence that mutations in this region and in other mitochondrial tRNA genes may cause disease.

Adult↗
PubMed1993

Smoking and mitochondrial function: a model for environmental toxins.

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity. We measured mitochondrial respiratory chain enzyme activities in platelets from 18 normal healthy non-smoking controls and compared them with those from 23 similarly healthy cigarette smoking individuals. A 24% decrease (p < 0.02) was observed in the mean NADH CoQ1 reductase (complex I) activity of the smoking group compared with that of the non-smoking group. There was no significant change in the activity of any of the other respiratory chain enzymes. This is the first demonstration in vivo of mitochondrial inhibition by a common environmental agent. The results offer a novel mechanism of action for the cellular toxicity, or even mutagenicity, associated with cigarette smoking. In addition, these data have important implications for the interpretation of platelet mitochondrial complex I activities in disease states. They are particularly relevant to our interpretation and understanding of the complex I deficiency in Parkinson's disease platelets.

Blood Platelets↗
PubMed1993

Evaluation of lung metabolism during successful twenty-four-hour canine lung preservation.

We used a canine left lung allotransplantation model to evaluate 24-hour lung preservation with two different electrolyte solutions, low-potassium dextran and low-potassium dextran with 1% glucose. To investigate changes in the energy status during preservation, we analyzed the lungs for adenosine triphosphate, phosphocreatine, and several metabolites of the glycolysis pathway and the citric acid cycle: glucose, glucose-6-phosphate, lactate, citrate, and malate. We also devised and evaluated a pulmonary cooling jacket to prevent rewarming of the lung during implantation. The lungs were divided into four groups. Groups I (n = 10) and II (n = 6) were flushed with low-potassium dextran and groups III (n = 6) and IV (n = 6) were flushed with low-potassium dextran solution with 1% glucose. The cooling jacket was used for groups II and IV only. After 24-hour preservation at 10 degrees C, the left lungs were implanted into the recipient animals. Function of the transplanted left lung was assessed during temporary (10 minutes) occlusion of the contralateral pulmonary artery while both lungs were ventilated with 100% oxygen. This assessment was performed at 1 hour and at 3, 8, and 22 days after transplantation. Immediately after transplantation the arterial oxygen tension was 279 +/- 70 mm Hg in group I, 376 +/- 56 mm Hg in group II, 523 +/- 41 mm Hg in group III, and 518 +/- 50 mm Hg in group IV. The arterial oxygen tension in groups III and IV were significantly greater than in group I (p < 0.05). Of the lungs preserved with low-potassium dextran solution with 1% glucose solution, 11 of 12 (92%) showed excellent lung function (arterial oxygen tension > 300 mm Hg) at 3 days; only 10 of 16 lungs preserved with low-potassium dextran achieved this level of function. Glucose, glucose-6-phosphate, lactate, citrate and malate levels decreased significantly during 24-hour preservation with low-potassium dextran solution; they were stable with low-potassium dextran solution with 1% glucose. Adenosine triphosphate and phosphocreatine were stable for 24 hours with both low-potassium dextran and low-potassium dextran solution with 1% glucose. The cooling jacket provided uniform cooling of the lung parenchyma during implantation, and significant increase in temperature was observed in its absence, with topical cooling by cold saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1993

Myopathy in vitamin E deficient rats: muscle fibre necrosis associated with disturbances of mitochondrial function.

Vitamin E deficiency in rats gives rise to a neuromuscular syndrome that includes a peripheral neuropathy as well as generalised muscle wasting and weakness. This is probably related to damage by oxygen-derived free radicals. In the present study, histological examination of lower limb muscles showed widespread myopathic changes which included the presence of amorphous electron-dense inclusions and tubular aggregates in muscle fibres and muscle fibre necrosis. Histochemical observations suggested a reduction in the activity of oxidative enzymes. The mitochondria showed nonspecific degenerative changes on electron microscopy; no paracrystalline inclusions were observed. Polarographic analysis of isolated muscle mitochondria revealed statistically significant decreases in oxygen utilisation rates with both NADH and FADH2-linked substrates. In confirmation of a generalised respiratory chain abnormality, enzymatic analyses revealed decreases in the activities of complexes I, II/III and IV, although only the decreases in complexes I and IV activities were statistically significant. Measurements of membrane fluidity showed that this is reduced in mitochondria from vitamin E deficient rats, indicating reduced stability of their membranes. The respiratory control ratio, derived from the polarographic results, was also reduced in mitochondria from vitamin E deficient animals, suggesting membrane damage. An altered lipid environment, possibly secondary to a higher level of lipid peroxidation, could result in the inhibition of complexes I and IV. This could also be caused by oxidative damage to the complexes or to mitochondrial DNA. The preservation of citrate synthase activity is against any generalised defect of mitochondrial function. The question as to whether these defects of mitochondrial respiratory chain function are responsible for the muscle fibre damage and necrosis requires further investigation.

Acid Phosphatase↗
PubMed1993

Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion.

We have studied cultured skin fibroblasts from a patient with a fatal mitochondrial disease manifesting soon after birth. These fibroblasts were found to grow only in the presence of pyruvate and uridine, a characteristic of cells lacking mtDNA (rho0 cells). Southern blot and PCR analyses confirmed that the patient's fibroblasts contained less than 2% of control levels of mtDNA. Biochemical analyses indicated that the activities of all the respiratory-chain enzymes were severely decreased in mitochondria isolated from these fibroblasts. In order to elucidate the underlying molecular defect, cell fusions were performed between enucleated fibroblasts from this patient and a human-derived rho0 cell line (rho0 A549.B2). The resulting cybrids were plated in medium lacking pyruvate and uridine, to select for the restoration of respiratory-chain function. Complementation was observed between the nuclear genome of the rho0 A549.B2 cells and the mtDNA of the patient's cells, restoring mtDNA levels and respiratory-chain function in the cybrid cells. These results indicate that mtDNA depletion in our patient is under the control of the nuclear genome.

Cell Fusion↗
PubMed1993

Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation. The maintenance of aerobic metabolism during lung preservation.

The lung is the only organ to which oxygen may be supplied after its blood supply is stopped. Before this study, we were not certain whether lung cells were able to maintain aerobic metabolism with the oxygen in the alveoli during preservation. Excised rabbit lungs were used to measure changes in the concentration of oxygen and carbon dioxide in the airway and changes in glucose, glucose-6-phosphate, lactate, adenosine triphosphate, and phosphocreatine levels in the lung tissue during preservation under different conditions. Twenty-seven lungs were flushed with low-potassium dextran electrolyte solution, inflated with room air, and preserved at 1 degree C (n = 8), 10 degrees C (n = 8), or 22 degrees (n = 11) for 4, 12, or 24 hours. Eight additional lungs were inflated with 100% nitrogen and preserved at 10 degrees C for 4 (n = 4) or 24 (n = 4) hours. Oxygen levels decreased and carbon dioxide levels increased in the airway of the lungs that were inflated with room air at rates dependent on the preservation temperature. The increase of carbon dioxide in the lungs that were inflated with 100% nitrogen was very small. When the oxygen was not available in the alveoli, lactate accumulated, and adenosine triphosphate and phosphocreatine decreased in the lung tissue. We concluded that lung cells are able to maintain aerobic metabolism with the oxygen in the alveoli during preservation and that the maintenance of aerobic metabolism may be essential to maintain the optimum viability of preserved lung tissue.

Adenosine Triphosphate↗