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At least 523 records · Page 29Linked to original sources
PubMed1999

The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate.

Cells harboring patient-derived mitochondria with an A-to-G transition at nucleotide position 3243 of their mitochondrial DNA display severe loss of respiration when compared with cells containing the wild-type adenine but otherwise identical mitochondrial DNA sequence. The amount and degree of leucylation of tRNA(Leu(UUR)) were both found to be highly reduced in mutant cells. Despite the low level of leucyl-tRNA(Leu(UUR)), the rate of mitochondrial translation was not seriously affected by this mutation. Therefore, decrease of mitochondrial protein synthesis as such does not appear to be a necessary prerequisite for loss of respiration. Rather, the mitochondrially encoded proteins seem subject to elevated degradation, leading to a severe reduction in their steady state levels. Our results favor a scheme in which the 3243 mutation causes loss of respiration through accelerated protein degradation, leading to a disequilibrium between the levels of mitochondrial and nuclear encoded respiratory chain subunits and thereby a reduction of functional respiratory chain complexes. The possible mechanisms underlying the pathogenesis of mitochondrial diabetes is discussed.

Cells, Cultured↗
PubMed1997

Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain.

Cisplatin-induced nephrotoxicity was studied in porcine proximal tubular cells, focusing on the relationship between mitochondrial damage, reactive oxygen species (ROS) and cell death. Cisplatin specifically affected mitochondrial functions: complexes I to IV of the respiratory chain were inhibited 15 to 55% after 20 min of incubation with 50 to 500 microM, respectively. As a result, intracellular ATP was decreased to 70%. The mitochondrial glutathione (reduced form) (GSH)-regenerating enzyme GSH-reductase (GSH-Rd) activity was reduced by 20%, which contributed to a 70% reduction of GSH levels and ROS formation. The residual electron flow through the mitochondrial respiratory chain was the source of ROS because additional inhibition of the complexes I to IV reduced ROS formation. Because cisplatin affects both GSH-Rd and complexes I to IV, cells were incubated with N,N'-bis(2-chloroethyl)-N-nitrosourea (inhibitor of GSH-Rd) and inhibitors of the different complexes. Only N,N'-bis(2-chloroethyl)-N-nitrosourea with rotenone (complex I inhibitor) induced ROS formation, which indicates that inhibition of complex I and inhibition of the GSH-Rd is probably the cause of ROS formation. However, the resulting ROS is not the cause of cell death because diphenyl-p-phenylene-diamine and deferoxamine, which completely prevented ROS, could not prevent cell death. Similarly, the antioxidants did not completely prevent the decrease in activity of complexes I to IV, ATP or GSH levels. In conclusion, ROS formation does occur during cisplatin-induced toxicity, but it is not the direct cause of cell death.

Adenosine Triphosphate↗
PubMed1995

The role of redox cycling versus arylation in quinone-induced mitochondrial dysfunction: a mechanistic approach in classifying reactive toxicants.

In an attempt to distinguish between the mechanisms by which electrophilic and redox cycling quinones induce the cyclosporine A (CyA)-sensitive mitochondrial membrane permeability transition, the ability of a series of quinones that span a broad range of electrophilic and redox cycling reactivities has been examined. The order of potency of quinone-induced Ca2+ release was 1,4-naphthoquinone (NQ) > 1,4-benzoquinone (BQ) > 2-methyl-1,4-naphthoquinone (MQ) > 2,3-dimethoxy-1,4-naphthoquinone (DiOMeNQ) > 2,3-dimethyl-1,4-naphthoquinone (DiMeNQ). Quinones with predominantly redox cycling reactivity, NQ ( < or = 4 microM), MQ, DiOMeNQ and DiMeNQ, induced the CyA-sensitive membrane permeability transition. In contrast, NQ ( > 4 microM) and BQ, induced rapid and complete Ca2+ release and membrane depolarization, but not swelling. Furthermore, BQ and NQ ( > 4 microM)-induced effects were not prevented by CyA. Therefore, we maintain that, unlike MQ, DiOMeNQ, DiMeNQ and NQ ( < or = 4 microM), effects of BQ and NQ( > 4 microM) on calcium flux and membrane potential are manifest via a mechanism independent of altering the regulation of the cyclosporine A-sensitive PTP. These findings suggest that stereoelectronic descriptors for soft electrophilicity and one electron reduction potential may be useful in differentiating and predicting mechanisms of quinone toxicity.

Animals↗
PubMed2007

Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice.

Heart mitochondria from female senescence-accelerated (SAMP8) and senescence-resistant (SAMR1) mice of 5 or 10 months of age, were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation, glutathione and glutathione disulfide and glutathione peroxidase and reductase activities. Mitochondrial function was assessed by measuring the activity of the respiratory chain complexes and ATP content. The results show that the age-dependent mitochondrial oxidative damage in the heart of SAMP8 mice was accompanied by a reduction in the electron transport chain complex activities and in ATP levels. Chronic melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased ATP levels. The results support the presence of significant mitochondrial oxidative stress in SAM mice at 10 months of age, and they suggest a beneficial effect of chronic pharmacological intervention with melatonin, which reduces the deteriorative and functional oxidative changes in cardiac mitochondria with age.

Adenosine Triphosphate↗
PubMed2002

Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.

Rich diet and lack of exercise are causing a surge in the prevalence of obesity and hepatic steatosis, which causes "primary" steatohepatitis in some patients. Ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and impaired ability to synthesize ATP are observed in these patients. Reactive oxygen species (ROS) may increase tumor necrosis factor-alpha (TNF-alpha) production and also oxidize fat deposits. TNF-alpha and lipid peroxidation products impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial ROS formation. Steatohepatitis can also be due to alcohol, drugs, or other causes that either directly increase ROS formation or first impair respiration, which secondarily increases ROS formation. Higher ROS formation in secondary steatohepatitis could cause more lipid peroxidation, cytokine induction, and fibrogenesis than in primary steatohepatitis.

Fats↗
PubMed1993

Mitochondrial dysfunction in yeast expressing the cytoplasmic male sterility T-urf13 gene from maize: analysis at the population and individual cell level.

The urf13TW gene, which is derived from the mitochondrial T-urf13 gene responsible for Texas cytoplasmic male sterility in maize, was expressed in Saccharomyces cerevisiae by targeting its translation product into mitochondria. Analysis by oxygraphy at the population level revealed that in the presence of methomyl the oxygen uptake of intact yeast cells carrying the targeted protein is strongly stimulated only with ethanol as respiratory substrate and not with glycerol, lactate, pyruvate, or acetate. When malate is the substrate oxidized by isolated mitochondria, interaction between the targeted protein and methomyl results in significant inhibition of oxygen uptake. This inhibition is eliminated and oxygen uptake is stimulated by subsequent addition of NAD+. Using 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] as probe, interactive laser scanning and flow cytometry, which permit analysis at the individual cell level, demonstrated that specific staining of the mitochondrial compartment is obtained and that DiOC6(3) fluorescence serves as a measure of the membrane potential. Finally, it was shown that, as in T cytoplasm maize mitochondria, HmT toxin and methomyl dissipate the membrane potential of yeast mitochondria that carry the foreign protein. Furthermore, the results suggest that the HmT toxin and methomyl response is related to the plasmid copy number per cell and that the deleterious effect induced by HmT toxin is stronger than that of methomyl.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1992

Mitochondrial dysfunction observed in situ in cardiomyocytes of rats in experimental diabetes.

OBJECTIVE: The aim was to investigate effects of experimental diabetes and insulin treatment on heart myocytes, particularly on the mitochondrial function studied in situ in isolated cardiomyocytes. METHODS: 20 male Sprague-Dawley rats (140-160 g) were made diabetic by intraperitoneal streptozotocin, 70 mg.kg-1. Ten then received daily subcutaneous injections of ultra lente insulin (starting dose of 3 units.d-1) for 7-15 d from the 20th day after streptozotocin. There was a control group of 11 rats. The rats were killed 21-35 d after the induction of diabetes, and heart myocytes were isolated by collagenase digestion. The 45[Ca]2+ uptake of mitochondria in situ in permeabilised myocytes, the transmembrane potential gradient of mitochondria, and the respiration of myocytes, as well as the cell yield and cell [45Ca]2+ uptake, were examined. RESULTS: Mitochondrial uptake of [45Ca]2+ was significantly decreased in the diabetic group compared to control at cytosolic calcium concentrations between 760 nM and 44.6 microM. The mitochondrial potential of diabetic myocytes, estimated from the distribution of [3H]triphenylmethylphosphonium+, was slightly but significantly decreased from the control value. Cell respiration, measured polarographically in the presence of pyruvate and malate or succinate as oxidisable substrates, and with or without 2,4-dinitrophenol, was decreased by diabetes. The rapidly exchangeable [45Ca]2+ content in the myocyte with intact sarcolemmal membrane ("cell Ca2+ uptake") and the yield of cells from heart tissue were also diminished in diabetic rats. These changes were returned to normal by insulin treatment of 7 d or longer. CONCLUSIONS: Insulin deficiency at early stages causes defects of mitochondrial function detectable in situ in cardiomyocytes. This suggests the possibility that such alterations are causative factors in the development of diabetic cardiomyopathy.

Animals↗
PubMed2003

Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions.

Nucleoside reverse transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are critical in current AIDS therapy, but mitochondrial side effects have come to light with the increased use of these compounds. Clinical experience, pharmacological, cell and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in specific target tissues are observed. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself. With increased use of NRTIs, mtDNA mutations may become increasingly important pathophysiologically. One important future goal is to prevent or attenuate the side effects so that improved efficacy is achieved.

Anti-HIV Agents↗
PubMed2000

Cardiomyopathy in childhood, mitochondrial dysfunction, and the role of L-carnitine.

Cardiomyopathy in childhood is associated with high morbidity and mortality rates. Many metabolic causes have been identified, including genetic or acquired defects in mitochondrial energy production affecting beta-oxidation, carnitine transport, and the electron transport chain. Combining conventional inotropic and antiarrhythmic therapy with metabolic interventions has improved overall outcome. L-carnitine, a natural substance involved in mitochondrial transport of fatty acids, is one such therapy and plays a central role in the regulation of the inner mitochondrial supply of free coenzyme A. Carnitine deficiency can be caused by both genetic and environmental causes with resultant signs and symptoms of metabolic disease, including cardiomyopathy. Administration of L-carnitine can result in improvement or resolution of the cardiomyopathy.

Cardiomyopathies↗
PubMed2002

Oxidative stress in preterm rat brain is due to mitochondrial dysfunction.

Prematurity-mediated cerebral damage has been associated with oxidative stress. The aim of the present work was to study the possible role played by free oxygen radicals generated by mitochondrial respiratory function in cerebral injury in preterm neonates. Our results show that whereas total glutathione concentrations are similar in term and preterm neonates, the GSH/GSSG ratio decreases sharply in preterm neonates immediately after birth. This effect is not due to a lack of enzymes involved in GSH regeneration, such as glutathione reductase and glucose-6-phosphate dehydrogenase, but to a significant increase in free-radical generation in preterm rat brain as shown by the increase in lipoperoxidation. Because the mitochondrion is the main source of free radicals in the cell, mitochondrial respiratory function was studied in the brain of preterm neonates. Our results show that prematurity prevented the postnatal increases in complex II-III activity and ATP concentrations that occur in term neonates at 5 min after delivery. All these effects were counteracted by the oxygen supply, suggesting that the inhibition of mitochondrial function is caused by restricted oxygen availability. Consequently, cerebral damage associated with prematurity may be mediated by mitochondrial free-radical generation as a consequence of hypoxia undergone by preterm neonates at birth.

Animals↗
PubMed2004

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani.

The parasites of the order kinetoplastidae including Leishmania spp. emerge from most ancient phylogenic branches of unicellular eukaryotic lineages. In their life cycle, topoisomerase I plays a significant role in carrying out vital cellular processes. Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces programmed cell death (PCD) both in the amastigotes and promastigotes form of L. donovani parasites. CPT-induced cellular dysfunction in L. donovani promastigotes is characterized by several cytoplasmic and nuclear features of apoptosis. CPT inhibits cellular respiration that results in mitochondrial hyperpolarization taking place by oligomycin-sensitive F0-F1 ATPase-like protein in leishmanial cells. During the early phase of activation, there is an increase in reactive oxygen species (ROS) inside cells, which causes subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents like GSH. Endogenous ROS formation and lipid peroxidation cause eventual loss of mitochondrial membrane potential. Furthermore, cytochrome c is released into the cytosol in a manner independent of involvement of CED3/CPP32 group of proteases and unlike mammalian cells it is insensitive to cyclosporin A. These events are followed by activation of both CED3/CPP32 and ICE group of proteases in PCD of Leishmania. Taken together, our study indicates that different biochemical events leading to apoptosis in leishmanial cells provide information that could be exploited to develop newer potential therapeutic targets.

Animals↗
PubMed1995

Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood.

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using 31P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turnover at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.

Adolescent↗
PubMed1997

Flow cytometric detection of mitochondrial dysfunction in subpopulations of human mononuclear cells.

At 488 nm argon-ion laser excitation human mononuclear cells emit flavoprotein-related autofluorescence signals. Approximately 60% of these are caused by the mitochondrial flavoproteins alpha-lipoamide dehydrogenase and electron transfer flavoprotein, having differences in their fluorescence emission spectra. At the emission wavelength of 530 nm the redox changes of alpha-lipoamide dehydrogenase fluorescence in human mononuclear cells can be monitored by flow cytometry. This allows the estimation of the steady-state reduction level of this flavoprotein being in redox equilibrium with the mitochondrial NAD-system. We applied this method to elucidate the possible impairment of mitochondrial function in subpopulations of mononuclear cells of patients harboring deletions of the mitochondrial DNA in skeletal muscle. In the monocyte fraction of three patients and in the lymphocyte fraction of one patient we observed in the presence of the mitochondrial substrate octanoate elevated steady-state reduction levels of alpha-lipoamide dehydrogenase. This is an indication for the presence of respiratory chain-inhibited mitochondria in mononuclear cell subpopulations of the described patients. These data were confirmed by conventional determinations of maximal oxygen consumption rates of digitonin-permeabilized cells. Therefore, the flow cytometric determination of flavoprotein-caused autofluorescence changes is a useful and sensitive method for the detection of an impairment of mitochondrial respiratory chain in subpopulations of heterogeneous cell suspensions.

Caprylates↗