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At least 487 records · Page 27Linked to original sources
PubMed1992

Disruption of mitochondrial function by suramin measured by rhodamine 123 retention and oxygen consumption in intact DU145 prostate carcinoma cells.

Suramin, an antiparasitic drug, has shown antitumor activity in humans. This may occur in part through disruption of energy balance, which is believed to be part of its antiparasitic action. Suramin disrupts mitochondrial function in intact DU145 prostate carcinoma cell monolayers as seen by its causing the release of rhodamine 123 from prestained cells beginning at about 10 microM in 96-well microtiter plates measured with a fluorescent plate scanner. This effect was similar to the ionophore carbonyl cyanide m-chlorophenylhydrazone, dissolved in ethanol at 0.01 N and indicates that suramin acts as a respiratory poison or an ionophore. This effect was confirmed by studies of oxygen consumption with a Clark oxygen electrode and cellular ATP content which demonstrated uncoupling of oxidative phosphorylation by 100 microM suramin, a clinically achievable plasma drug level.

Adenosine Triphosphate↗
PubMed2003

Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress.

Amphetamine-like psychostimulants are associated with long-term decreases in markers for monoaminergic neurons, suggesting neuronal loss and/or damage within the brain. This long-term "toxicity" results from formation of free radicals, particularly reactive oxygen species (ROS) and reactive nitrogen species (RNS), although the mechanism(s) of ROS and RNS formation are unclear. Mitochondria are a major source of ROS and mitochondrial dysfunction has been linked to some neurodegenerative disorders. Amphetamines also inhibit mitochondrial function, although the mechanism involved in the inhibition is uncertain. This review coordinates findings on the multiple pathways for ROS and RNS and describes a hypothesis involving mitochondrial inhibition in the initiation of amphetamine-induced cellular necrosis.

Amphetamines↗
PubMed2000

Intrafollicular influences on human oocyte developmental competence: perifollicular vascularity, oocyte metabolism and mitochondrial function.

While genetic and epigenetic factors have been associated with the developmental competence of human oocytes and embryos produced by IVF, how such factors develop or influence the oocyte remain to be explained. This paper reviews evidence which suggests that the degree of perifollicular vascular expansion associated with increased rates of blood flow are developmentally important for the generation of a normal follicle and competent oocyte. The degree of vascular development is follicle specific and differences between follicles might reflect their unique abilities to regulate angiogenic growth factor(s) production by the follicle cells in response to hypoxia. The notion that mitochondrial function in oocytes and early embryos could be influenced by intrafollicular conditions, and that differential patterns of mitochondrial segregation occur in blastomeres during early cleavage, is discussed with respect to the role of these organelles as critical determinants of developmental competence.

Embryo, Mammalian↗
PubMed2004

Determination of mitochondrial function and site-specific defects in electron transport in duodenal mitochondria in broilers with low and high feed efficiency.

Duodenal mitochondria were isolated from broiler breeder males with high (0.79+/-0.01, n = 9) and low (0.63+/-0.02, n = 9) feed efficiency (FE) to assess relationships of FE with duodenal mitochondrial function and site-specific defects in electron transport. Sequential additions of adenosine diphosphate (ADP) resulted in 1) higher respiratory control ratio (RCR; an index of respiratory chain coupling) in high FE mitochondria provided succinate, and 2) higher ADP to oxygen ratio (ADP:O; an index of oxidative phosphorylation) in low FE mitochondria provided NADH-linked substrates (malate, pyruvate, or both). Basal electron leak, measured as H2O2 production, was greater in low FE mitochondria provided succinate (P = 0.08) or NADH-linked substrates. As H2O2 levels were elevated in low FE compared with high FE mitochondria by complex I (P+/-0.07) and complex II inhibition, the higher basal electron leak in low FE mitochondria was apparently due to site-specific defects in electron transport at complexes I and II. Elevations in H2O2 above basal levels indicated that high FE mitochondria may also exhibit electron transport defects at complexes I and III. Despite an ability to produce adenosine triphosphate (ATP) that was equal or superior to that demonstrated in high FE duodenal mitochondria, low FE mitochondria exhibited a greater inherent degree of electron leak. The results provide insight into the role that duodenal mitochondria play in the phenotypic expression of FE in broilers.

Adenosine Diphosphate↗
PubMedDate not supplied

HPMA copolymer-bound doxorubicin induces apoptosis in ovarian carcinoma cells by the disruption of mitochondrial function.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin has showed greater potency than free doxorubicin in the treatment of ovarian cancer in vivo and in vitro. The promising activity of the conjugate demonstrated in clinical trials has generated considerable interest in understanding the mechanism of action of this macromolecular therapeutic. In this study, the involvement of the mitochondrial pathway in HPMA copolymer-bound doxorubicin-induced apoptosis in the human ovarian cancer cell line A2780 was investigated. Through a series of in vitro assays, including confocal microscopy, flow cytometry, and spectrofluorimetry, a significant decrease in mitochondrial membrane potential in A2780 cells treated with HPMA copolymer-bound doxorubicin was found. The most dramatic changes in mitochondrial membrane potential were observed between 2 and 12 h of continuous drug exposure. The potential of the mitochondrial membrane remained collapsed when drug treatment continued up to 24 h. For the first time, it was shown that HPMA copolymer-bound doxorubicin induces apoptosis in ovarian cancer cells by simultaneous activation of both caspase-dependent and caspase-independent pathways of DNA damage. This was determined by monitoring the translocation of the mitochondrial proteins cytochrome c and apoptosis-inducing factor to cytosol. The altered balance between anti-apoptotic and pro-apoptotic members of the Bcl-2 family of proteins was responsible for the mitochondrial function distraction. HPMA copolymer-bound doxorubicin induced a time-dependent decrease in the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins, which control cell survival. At the same time, the expression level of pro-apoptotic members (Bax, Bad) of the Bcl-2 family was increased under the chosen experimental conditions. Altogether, these results indicate that HPMA copolymer-bound doxorubicin induced apoptosis in ovarian cancer cells through the mitochondrial pathway.

Acrylamides↗
PubMed2002

Physical exercise and mitochondrial function in human skeletal muscle.

Muscle adaptation to endurance training involves qualitative changes in intrinsic properties of mitochondria. After training, the ADP sensitivity of miitochondrion is decreased whereas the effect of creatine on respiration is increased. This results in an improved control of aerobic energy production. Acute exercise does not adversely affect mitochondrial function.

Adenosine Diphosphate↗
PubMed2001

Disruption of mitochondrial function and cellular ATP levels by amiodarone and N-desethylamiodarone in initiation of amiodarone-induced pulmonary cytotoxicity.

Amiodarone (AM), a potent antidysrhythmic agent, can cause potentially life-threatening pulmonary fibrosis. In the present investigation of mechanisms of initiation of AM lung toxicity, we found that 100 microM AM decreased mitochondrial membrane potential in intact hamster lung alveolar macrophages and preparations enriched in isolated alveolar type II cells and nonciliated bronchiolar epithelial (Clara) cells, following 2 h of incubation. This was followed by a drop in cellular ATP content (by 32--77%) at 4 to 6 h, and 30 to 55% loss of viability at 24 h. Supplementation of incubation media with 5.0 mM glucose or 2.0 mM niacin did not reduce AM-induced ATP depletion or cell death in macrophages, and the mitochondrial permeability transition inhibitor cyclosporin A (1.0 microM) did not affect AM cytotoxicity. At 50 microM, the AM metabolite N-desethylamiodarone (DEA) produced effects similar to those of AM, but more rapidly and extensively, with the Clara cell-enriched preparation being particularly susceptible. In isolated whole lung mitochondria, DEA was accumulated to a greater extent than AM. Both AM and DEA inhibited complex I- and complex II-supported respiration, but DEA inhibited complex II to a greater degree than AM. These results demonstrate that AM and DEA disrupt mitochondrial membrane potential prior to ATP depletion and subsequent lung cell death, that DEA is more potent than AM, and that the mitochondrial permeability transition is not involved in mitochondrial perturbation by AM. This suggests that AM- and DEA-induced perturbations of mitochondrial function may initiate AM-induced pulmonary toxicity.

Adenosine Triphosphate↗
PubMed2006

Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function.

Developing oligodendrocytes (OL precursors, pre-OLs) express alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype glutamate receptors (AMPARs) and are highly vulnerable to hypoxic-ischemic or oxygen-glucose deprivation (OGD)-induced excitotoxic injury, yet the mechanisms of injury remain unclear. Here we investigated the role of glutamate accumulation and mitochondrial function in OGD-induced pre-OL toxicity in vitro. Bulk glutamate concentration in the culture medium did not increase during OGD and OGD-conditioned medium did not transfer toxicity to naïve cells. Facilitation of glutamate diffusion by constant agitation of the culture reduced, while inhibition of glutamate diffusion by increasing medium viscosity with dextran enhanced, OGD-induced pre-OL injury. Depletion of extracellular glutamate by the glutamate scavenging system, glutamate-pyruvate transaminase plus pyruvate, attenuated pre-OL injury during OGD. Together these data suggest that local glutamate accumulation is critical for OGD toxicity. Interestingly, under normoxic conditions, addition of glutamate to pre-OLs did not cause receptor-mediated toxicity, but the toxicity could be unmasked by mitochondrial impairment with mitochondrial toxins. Furthermore, OGD caused mitochondrial potential collapse that was independent of AMPAR activation, and OGD toxicity was enhanced by mitochondrial toxins. These data demonstrate that pre-OL excitotoxicity is exacerbated by mitochondrial dysfunction during OGD. Overall, our results indicate that OGD-induced pre-OL injury is a novel form of excitotoxicity caused by the combination of local glutamate accumulation that occurs without an increase in bulk glutamate concentration and mitochondrial dysfunction. Therapeutic strategies targeting local glutamate concentration and mitochondrial injury during hypoxia-ischemia may be relevant to human disorders associated with pre-OL excitotoxicity.

Animals↗
PubMed2004

Cadmium effects on mitochondrial function are enhanced by elevated temperatures in a marine poikilotherm, Crassostrea virginica Gmelin (Bivalvia: Ostreidae).

Marine intertidal mollusks, such as oysters, are exposed to multiple stressors in estuaries, including varying environmental temperature and levels of trace metals, which may interactively affect their physiology. In order to understand the combined effects of cadmium and elevated temperature on mitochondrial bioenergetics of marine mollusks, respiration rates and mitochondrial volume changes were studied in response to different cadmium levels (0-1000 micromol l(-1)) and temperatures (15, 25 and 35 degrees C) in isolated mitochondria from the eastern oyster Crassostrea virginica acclimated at 15 degrees C. It was found that both cadmium and temperature significantly affect mitochondrial function in oysters. Elevated temperature had a rate-enhancing effect on state 3 (ADP-stimulated) and states 4 and 4+ (representative of proton leak) respiration, and the rate of temperature-dependent increase was higher for states 4 and 4+ than for state 3 respiration. Exposure of oyster mitochondria to 35 degrees C resulted in a decreased respiratory control and phosphorylation efficiency (P/O ratio) compared to that of the acclimation temperature (15 degrees C), while an intermediate temperature (25 degrees C) had no effect. Cadmium exposure did not lead to a significant volume change in oyster mitochondria in vitro. Low levels of cadmium (1-5 micromol l(-1)) stimulated the rate of proton leak in oyster mitochondria, while not affecting ADP-stimulated state 3 respiration. In contrast, higher cadmium levels (10-50 micromol l(-1)) had little or no effect on proton leak, but significantly inhibited state 3 respiration by 40-80% of the control rates. Elevated temperature increased sensitivity of oyster mitochondria to cadmium leading to an early inhibition of ADP-stimulated respiration and an onset of complete mitochondrial uncoupling at progressively lower cadmium concentrations with increasing temperature. Enhancement of cadmium effects by elevated temperatures suggests that oyster populations subjected to elevated temperatures due to seasonal warming or global climate change may become more susceptible to trace metal pollution, and vice versa.

Analysis of Variance↗
PubMedDate not supplied

Mitochondrial function in seasonal acclimatization versus latitudinal adaptation to cold in the lugworm Arenicola marina (L.).

Previous studies in marine ectotherms from a latitudinal cline have led to the hypothesis that eurythermal adaptation to low mean annual temperatures is energetically costly. To obtain more information on the trade-offs and with that the constraints of thermal adaptation, mitochondrial functions were studied in subpolar lugworms (Arenicola marina L.) adapted to summer cold at the White Sea and were compared with those in boreal specimens from the North Sea, either acclimatized to summer temperatures or to winter cold. During summer, a comparison of mitochondria from subpolar and boreal worms revealed higher succinate oxidation rates and reduced Arrhenius activation energies (Ea) in state 3 respiration at low temperatures, as well as higher proton leakage rates in subpolar lugworms. These differences reflect a higher aerobic capacity in subpolar worms, which is required to maintain motor activity at low but variable environmental temperatures--however, at the expense of an elevated metabolic rate. The lower activity of citrate synthase (CS) found in subpolar worms may indicate a shift in metabolic control within mitochondria. In contrast, acclimatization of boreal lugworms to winter conditions elicited elevated mitochondrial CS activities in parallel with enhanced mitochondrial respiration rates. With falling acclimation temperatures, the significant Arrhenius break temperature in state 3 respiration (11 degrees C) became insignificant (5 degrees C) or even disappeared (0 degrees C) at lower levels of Arrhenius activation energies in the cold, similar to a phenomenon known from hibernating vertebrates. The efficiency of aerobic energy production in winter mitochondria rose as proton leakage in relation to state 3 decreased with cold acclimation, indicated by higher respiratory control ratio values and increased adenosine diphosphate/oxygen (ADP/O) ratios. These transitions indicate reduced metabolic flexibility, possibly paralleled by a loss in aerobic scope and metabolic depression during winter cold. Accordingly, these patterns contrast those found in summer-active, cold-adapted eurytherms at high latitudes.

Acclimatization↗
PubMed2005

IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes.

OBJECTIVE: Interleukin-6 (IL-6) is a pro-inflammatory cytokine which is a prognostic marker associated with left ventricular contractile dysfunction and heart failure. On the other hand, IL-6 activates signalling pathways which mediate delayed ischemic preconditioning. We have therefore studied the cellular mechanisms of IL-6-induced cardioprotection. METHODS: Inducible nitric oxide synthase (iNOS) expression, cardiomyocyte calcium handling, mitochondrial energetics, and the activation of protective signalling pathways in response to IL-6 were studied in a model of simulated ischemia/reperfusion (sI/R) in isolated neonatal rat ventricular cardiomyocytes. RESULTS: Reperfusion after sI/R induced a rise in cytosolic [Ca2+], a loss of cell morphology and integrity, and a transient increase in mitochondrial potential (Deltapsi m), followed by mitochondrial swelling and collapse of Deltapsi m. Pre-treatment of cardiomyocytes with 10 ng/ml IL-6 for 6 h, 24 h prior to sI/R prevented the secondary rise in cytosolic [Ca2+] and induced expression of iNOS and NO-dependent protection against sI/R injury. The protection against sI/R was concomitant with a NO-dependent reduction in the amplitude of cytosolic Ca2+ transients. IL-6 induced an increase in inner mitochondrial membrane polarisation and increased mitochondrial Ca2+ loading (rhod-2 fluorescence) at baseline, but prevented the reperfusion-induced changes in mitochondrial function. IL-6 pre-treatment also resulted in activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and both iNOS induction and IL-6-dependent protection were blocked by the PI 3-kinase inhibitor wortmannin. CONCLUSION: IL-6 induces a PI 3-kinase and NO-dependent protection of cardiomyocytes, which is associated with alterations in mitochondrial Ca2+ handling, inhibition of reperfusion-induced mitochondrial depolarisation, swelling and loss of structural integrity, and suppression of cytosolic Ca2+ transients.

Androstadienes↗
PubMed2005

Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice.

Male mice receiving vitamin E (5.0 g alpha-tocopherol acetate/kg of food) from 28 wk of age showed a 40% increased median life span, from 61 +/- 4 wk to 85 +/- 4 wk, and 17% increased maximal life span, whereas female mice equally supplemented exhibited only 14% increased median life span. The alpha-tocopherol content of brain and liver was 2.5-times and 7-times increased in male mice, respectively. Vitamin E-supplemented male mice showed a better performance in the tight-rope (neuromuscular function) and the T-maze (exploratory activity) tests with improvements of 9-24% at 52 wk and of 28-45% at 78 wk. The rates of electron transfer in brain mitochondria, determined as state 3 oxygen uptake and as NADH-cytochrome c reductase and cytochrome oxidase activities, were 16-25% and 35-38% diminished at 52-78 wk. These losses of mitochondrial function were ameliorated by vitamin E supplementation by 37-56% and by 60-66% at the two time points considered. The activities of mitochondrial nitric oxide synthase and Mn-SOD decreased 28-67% upon aging and these effects were partially (41-68%) prevented by vitamin E treatment. Liver mitochondrial activities showed similar effects of aging and of vitamin E supplementation, although less marked. Brain mitochondrial enzymatic activities correlated negatively with the mitochondrial content of protein and lipid oxidation products (r2 = 0.58-0.99, P < 0.01), and the rates of respiration and of complex I and IV activities correlated positively (r2 = 0.74-0.80, P < 0.01) with success in the behavioral tests and with maximal life span.

Aging↗
PubMed2006

An efficient genetic screen in Drosophila to identify nuclear-encoded genes with mitochondrial function.

We conducted a screen for glossy-eye flies that fail to incorporate BrdU in the third larval instar eye disc but exhibit normal neuronal differentiation and isolated 23 complementation groups of mutants. These same phenotypes were previously seen in mutants for cytochrome c oxidase subunit Va. We have molecularly characterized six complementation groups and, surprisingly, each encodes a mitochondrial protein. Therefore, we believe our screen to be an efficient method for identifying genes with mitochondrial function.

Alkyl and Aryl Transferases↗
PubMed1990

Selective alteration of mitochondrial function by Ditercalinium (NSC 335153), a DNA bisintercalating agent.

The bifunctional intercalator Ditercalinium (NSC 335153) demonstrates an anti-tumoral cytotoxicity markedly different from other intercalating agents. A delayed toxicity is observed in eucaryotic cells, both in vitro and in vivo, at drug concentrations far below those required to observe immediate toxic effects. Fluorescence microscopy demonstrates that Ditercalinium and the mitochondrial-staining fluorophore DiOC2(5) are concentrated in the same cellular organelles of L1210 cells. Electron microscopy of Ditercalinium-treated cells reveals extensive and progressive swelling of mitochondria, with no other ultrastructural changes observed. Ditercalinium uptake and toxicity are in part related to mitochondrial membrane potential. However, drug accumulation itself does not immediately alter the mitochondrial membrane potential. Cellular ATP pool levels and the rate of respiration fall progressively after drug treatment. Nucleotide pools in DC3F cells, measured between drug treatment and death, show marked drops in pyrimidine levels while purine nucleotide levels decline more slowly. Addition of uridine or cytidine partially rescues Ditercalinium-treated cells, while toxicity is increased in the presence of 2-deoxyglucose. The combined evidence indicates that the toxicity of Ditercalinium to murine leukemia cells (L1210) and Chinese Hamster lung cells (DC3F) is due to disruption of mitochondrial function.

Adenosine Triphosphate↗
PubMed1971

Oxidative phosphorylation. The relation between the specific binding of trimethylytin and triethyltin to mitochondria and their effects on various mitochondrial functions.

1. A binding site (site 1) is present in mitochondria with affinity for trimethyltin and triethyltin adequate for a site to which they could be attached when the processes of energy conservation are inhibited. 2. The quantitative relationships between the binding of trimethyltin and triethyltin to site 1 and their effects on various mitochondrial functions have been examined. 3. ATP synthesis linked to the oxidation of pyruvate, succinate and intramitochondrial substrate, ATP synthesis and oxygen uptake (succinate or pyruvate as substrate) stimulated by uncoupling agents are all inhibited by trimethyltin and triethyltin; when inhibition is less than 50% the ratio (percentage inhibition)/(percentage of binding site 1 complexed) is approx. 10:1. 4. ATP synthesis linked to the oxidation of reduced cytochrome c (ascorbate+NNN'N'-tetramethyl-p-phenylenediamine), ATP hydrolysis and oxygen uptake in the presence of low concentrations of trimethyltin and triethyltin approach zero activity as the proportion of binding site 1 complexed approaches 100%. 5. Possible interpretations of these findings are discussed with reference to published arrangements for coupling of electron transport to ATP synthesis and also to our present knowledge of the chemical and biological specificity of trialkyltin compounds.

Adenosine Triphosphate↗
PubMed1984

Dietary trans-fatty acid effects on mitochondrial functionality and phospholipid composition in rat perfused hearts in oxygenation and anoxia.

Dietary fatty acid fraction influence on heart composition is known and we have previously demonstrated a trans-fatty acid accumulation in heart. In this work we will verify trans-fatty acid effect on heart phospholipid fatty acid composition and miocardic mitochondrial respiratory activity under the influence of perfusion techniques in oxygenation and anoxic conditions. Results have pointed out, in group fed with 28% trans-fatty acid hydrogenated fat, a decreased mitochondrial functionality during perfusion in different oxygenation condition, probably correlated to different fatty acid composition of heart phospholipids.

Animals↗
PubMed1995

Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: effects on the energy state and mitochondrial function.

Rat hearts, arrested in situ after intracaval injection of a cardioplegic solution, were preserved for 15 hours at 4 degrees C either by simple immersion or by low-flow (0.3 mL/min) perfusion. After preservation under both conditions, the left ventricular pressure developed by the reperfused hearts reached 8% and 43% of the control value (80 mm Hg), respectively. The addition of trimetazidine (TMZ; 10(-6) M) to the cardioplegic solution induced an improvement in functional recovery (by 2.4 and 1.5, respectively). This effect of TMZ was accompanied by a better energy profile illustrated by a 2-fold increase in the adenosine triphosphate to inorganic phosphate ratio and a reduction of intracellular acidosis as determined by 31P nuclear magnetic resonance spectroscopy. The function of the mitochondria (state 3, reduced nicotinamide-adenine dinucleotide [NADH] formation) isolated from the preserved hearts was significantly depressed in the stored hearts. The addition of TMZ to the cardioplegic solution partially protected oxoglutarate (and succinate) mitochondrial respiration and induced an increase in Ca2+ triggered NADH formation. These results show that the bioenergy status of the myocardial cell in isolated arrested stored rat heart is improved by the presence of TMZ in the preservation solution. Moreover, the experiments demonstrate that this effect includes protection of mitochondrial function and suggest that the drug could exert some control in the Ca2+ regulation of mitochondria.

Analysis of Variance↗