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Biomedical subjects

F Cardellach

Publications and source records attributed to F Cardellach.

At least 37 records · Page 2Linked to original sources
PubMed1998

Biochemical and molecular effects of chronic haloperidol administration on brain and muscle mitochondria of rats.

The objectives of the current study were to evaluate (1) the respiratory rates and enzyme activities of brain and muscle mitochondria from rats chronically treated with haloperidol, (2) the protective role of dopamine (DA) D-1 (SKF38393) and D-2 (quinpirole) receptor agonists, and (3) the effect of haloperidol on the mitochondrial DNA (mtDNA) and protein synthesis. Thirty male Sprague-Dawley rats were subdivided into the following five groups: controls, haloperidol, haloperidol plus SKF38393, haloperidol plus quinpirole, and haloperidol plus SKF38393 and quinpirole. We compared the respiratory rates and enzymatic activities of brain and muscle mitochondria from controls with other groups. We finally analyzed the mitochondrial protein synthesis and mtDNA alterations (deletions, point mutations, and depletion) in two rats from each group. In brain but not in muscle from haloperidol-treated rats, we found a decrease of oxygen consumption rates using glutamate plus malate (-68 +/- 35%, P < 0.05) and succinate (-78 +/- 20%, P < 0.05) as substrates as well as low complex I, II, and V activities (-35 +/- 15%, P < 0.05; -54 +/- 13%, P < 0.05; and -60 +/- 33%, P < 0.01; respectively). The administration of SKF38393 alone or together with quinpirole prevented most of haloperidol-induced effects, whereas the protective effects of quinpirole alone were lower. Brain mitochondrial protein synthesis was decreased in haloperidol-treated rats and was not prevented by SKF38393, quinpirole, or both. We did not find mtDNA abnormalities in brain or muscle mitochondria from haloperidol-treated rats. Chronic administration of haloperidol in rats is associated with a nonspecific deleterious effect in the activity of electron transport chain of brain, and this effect is only partially prevented by DA D-1 agonists. These results suggest that other mechanisms different from DA receptors pathway can contribute to the expression of behavioral supersensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Cytochrome c oxidase assay in minute amounts of human skeletal muscle using single wavelength spectrophotometers.

Determination of cytochrome c oxidase (COX; EC 1.9.3.1) activity in human mitochondria presents several technical difficulties which result in a large intra- and interlaboratory variability, especially when a single wavelength spectrophotometer (SWS) is used, as is generally done in most laboratories in the context of screening procedures for the detection of respiratory chain deficiencies. We studied the experimental conditions of COX assay in human skeletal muscle mitochondria using a SWS in order to define the optimal conditions for the assay and compared these results with those obtained using a double wavelength spectrophotometer (DWS). We demonstrate that a low intra-individual variability of COX assay can be obtained with SWS by: (1) using manual stirrers to avoid the formation of bubbles in the mixture; (2) preincubating mitochondria and laurylmaltoside before the addition of cytochrome c, which prevents light scattering secondary to mitochondrial swelling; and (3) using low amounts (1-2 microg) of mitochondrial protein to extend and linearize the reaction rate. Under these experimental conditions, the concordance between SWS and DWS was very good (R=0.975).

Electron Transport↗
PubMed1998

Biochemical parameters for the diagnosis of mitochondrial respiratory chain deficiency in humans, and their lack of age-related changes.

It is now widely acknowledged that a large number of human diseases originate from respiratory-chain dysfunctions. Because the molecular bases of these diseases are still poorly known, a biochemical approach has to be used in the screening procedures for the diagnoses of these conditions. Assessment of respiratory-chain function in human samples faces several problems: (i) the small size of available samples, (ii) the determination of discriminating parameters, and (iii) the interfering factors, such as age and physical activity. The present study focuses on isolated mitochondria prepared from a minute amount (100-200 mg) of skeletal-muscle biopsies from 201 patients between 0 and 65 years. Whereas 42 patients presented an isolated complex (C)I, CII, CIII or CIV deficiency, no respiratory-chain dysfunction or indirect evidence for a mitochondrial disorder could be attested in 159 of these patients. In this reference group, there was little correlation between enzyme activities and age, whatever the age class considered, 0-3 or 0-65 years of age. However, a confident handling of data points was largely hampered by the marked scattering of enzyme activities measured in the reference population. Activity ratios between the various respiratory-chain complexes presenting a much reduced scattering may be considered as diagnostic tools. As to the effect of age, no correlation with any of the enzyme-activity ratios could be shown. Use of age-matched controls for the diagnosis of respiratory-chain disorders may therefore be avoided, enzyme-activity ratios being highly discriminating and age-independent parameters.

Adolescent↗
PubMed1998

Mitochondrial cytochrome c oxidase inhibition during acute carbon monoxide poisoning.

Clinical symptoms of acute carbon monoxide (CO) poisoning are mainly related to the capability of haemoglobin to bind CO. However, the persistence of some clinical alterations after carboxyhaemoglobin normalization suggests that other heme containing proteins, like cytochrome c oxidase, could play a role in its pathogenesis. We studied mitochondrial enzyme activities of lymphocytes from three patients suffering from acute CO poisoning. HbCO levels were 11.6%. 19.6% and 22.3% in the acute phase, 2.3%, 2.4% and 1.5% on day 3 after admission, and 1.2%, 3.3% and 1.1% on day 12. Complex II, III and glycerol-3-phosphate dehydrogenase activities remained normal along the study, while cytochrome c oxidase (complex IV) activity showed a 76% inhibition compared to controls during acute poisoning (P < 0.01) and 48% at day 3 (P < 0.05). The activity was normal already on day 12 after the complete disappearance of symptomatology. Our results suggest that mitochondrial cytochrome c oxidase is also a target site in human acute CO poisoning, and its extended and generalized inhibition could explain the persistence of different symptoms after the normalization of HbCO levels.

Acute-Phase Proteins↗
PubMed1998

[Secondary mitochondrial diseases].

OBJECTIVE: To analyze the secondary mitochondriopathies, which are processes characterized by the presence of structural and/or functional abnormalities of mitochondria whose causes may be assumed to be situated outside these organella. DEVELOPMENT: These processes will be categorized in the following groups; 1. Specific deficiency of a intermediate metabolite or cofactor; 2. Endocrinopathies; 3. Ischemia-reperfusion; 4. Sepsis; 5. Toxins; 6. Drugs; 7. Mitochondrial respiratory chain deficiency; 8. Ageing, and 9. Oncogenesis and apoptosis. CONCLUSION: The better understanding of secondary mitochondriopathies may allow to eliminate the cause of them and sometimes to establish the appropriate treatment.

Electron Transport↗
PubMed1998

Histological and biochemical assessment of mitochondrial function in dermatomyositis.

OBJECTIVE: Mitochondrial dysfunction in idiopathic inflammatory myopathies (IIM) remains a controversial issue. The aim of the present study was to investigate the correlation between histological abnormalities and the biochemical function of the skeletal muscle mitochondria from patients with dermatomyositis (DM). METHOD: We evaluated 10 patients with a new diagnosis of DM and 15 healthy individuals, matched by age and gender. Muscle biopsy was routinely processed for histochemical studies and biochemical analysis of pure mitochondria. The percentages of ragged-red fibres (RRF), cytochrome c oxidase (COX)-negative fibres and succinic dehydrogenase (SDH) hyper-reactive fibres were calculated, oxygen utilization using different substrates was assessed polarographically, and enzymatic activity of individual complexes of the electron transport chain (ETC) and ATPase was measured spectrophotometrically. RESULTS: We found an increased percentage of COX-negative and SDH hyper-reactive fibres in DM patients (0.82 and 1.82%, respectively) compared to controls (0.26 and 0.22%; P < 0.05 and P = 0.001, respectively); however, oxidation rates of different substrates and enzymatic activities of ETC and ATPase did not differ significantly between both groups. CONCLUSION: The overall function of ETC from skeletal muscle mitochondria is not affected in DM.

Adenosine Triphosphatases↗
PubMed1997

Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging.

The contribution of the mitochondrial genetic system in the degenerative processes of senescence remains unclear. This study deals with age-related changes in brain mtDNA expression in humans. Brain tissue from the frontal lobe cortex was obtained from autopsy of 13 humans aged between 21 and 84 years. No structural changes were detected in mtDNA, increased mtDNA content and reduced steady-state level of mitochondrial transcripts and transcription ratio (mtRNA/mtDNA) were associated with aging. These findings suggest that the increase of the mtDNA levels could be considered as an inefficient compensatory mechanism to maintain the normal levels of mtRNA transcripts. This unbalanced mitochondrial condition could play a role in the process of senescence in human brain.

Adult↗
PubMed1997

Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process.

It has been widely postulated that age-dependent changes in the mitochondrial genetic system may contribute to the human aging process. We recently reported unchanged specific activities of mitochondrial respiratory chain enzymes and a decrease in oxidation capacity of different substrates with aging, due, in part, to some confounding variables such as physical activity or tobacco consumption. The present study deals with age-related changes in muscle mtDNA structure and its biogenesis in humans. We found a low prevalence of mtDNA rearrangements with aging, only detected by PCR. The mtDNA content increased significantly with age (b = 0.0115, P < 0.0001). Also, an unchanged steady-state level of mitochondrial transcripts, a reduced transcription rate (P < 0.0001), and an increase in mitochondrial membrane lipid peroxidation (P < 0.0001) were observed in aging. These data demonstrate that minor structural mtDNA changes appear during the human aging process. By contrast, alterations in mitochondrial homeostasis ultimately producing modifications in mitochondrial biogenesis rates could play a role in the process of human senescence.

Adult↗
PubMed1997

Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene.

Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma (CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer.

Adult↗
PubMed1997

Respiratory chain activity and mitochondrial DNA content of nonpurified and purified pancreatic islet cells.

Considerable interest has recently focused on the possible role of alterations in mitochondrial activity and mutations in the mitochondrial genome for the development of non-insulin-dependent diabetes. Our study aimed at investigating the normal mitochondrial respiratory chain activity of nonpurified and purified islet cells to further explore whether some diabetic states are associated with alterations of mitochondrial oxidative processes. For this purpose, pancreatic islets were isolated from Wistar rats. Unpurified islet cells were obtained in the presence of trypsin and DNAse, and purified beta and non-beta cells were prepared by autofluorescence-activated sorting using a flowcytometer. Intact cell respiration and substrate oxidation in digitonin-permeabilized cells were measured polarographically with a Clark oxygen electrode in a micro-water-jacketed cell. Specific activity of the individual complexes of the respiratory chain was determined spectrophotometrically in unpurified islet cells. The relative amount of mitochondrial (mtDNA) and nuclear (nDNA) DNA in all three cell populations and in rat brain and skeletal muscle was estimated by dot blotting. The intact cell respiration of unpurified islet cells corresponds to the mean of values obtained for beta and non-beta islet cells. Oxidation rates of different substrates by permeabilized beta cells were lower than those for unpurified and non-beta cells. The amount of mtDNA relative to nDNA was similar in all three groups of cells, and was also similar to that obtained from brain and skeletal muscle. In summary, we have described mitochondrial respiratory chain activity in unpurified, beta, and non-beta islet cells. Our results represent an initial step in investigating the potential pathogenic role that alterations in oxidative phosphorylation could play in some diabetic states.

Animals↗
PubMed1996

Absence of relationship between the level of electron transport chain activities and aging in human skeletal muscle.

We investigated the relationship between age and respiratory chain function of skeletal muscle mitochondria in 132 control individuals (15 to 95 years old). Muscle mitochondria were studied polarographically and spectrophotometrically. By regression analysis, we found a significant inverse correlation between age and oxygen uptake linked to substrate oxidation (succinate, glutamate-malate or ascorbate-TMPD). However, this significance disappeared after including physical activity and tobacco consumption as confounding variables in a multivariate statistical analysis. Similarly, the activity of respiratory chain complexes individually measured did not decline with age. It therefore appears that respiratory chain activity in human skeletal muscle mitochondria is substantially undamaged during the aging process.

Adolescent↗