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At least 883 records · Page 49Linked to original sources

PubMed2002

Ciclopirox prevents peroxynitrite toxicity in astrocytes by maintaining their mitochondrial function: a novel mechanism for cytoprotection by ciclopirox.

Previously we have reported that astrocytes deprived of glucose were highly vulnerable to peroxynitrite (Choi and Kim, J. Neurosci. Res. 54 (1998) 870; Neurosci. Lett. 256 (1988) 109; Ju et al., J. Neurochem. 74 (2000) 1989). Here we report that ciclopirox, which is clinically used as an anti-fungal agent, completely prevents the increased death in glucose-deprived astrocytes exposed to 3-morpholinosydnonimine (SIN-1, a peroxynitrite-releasing reagent). The increased vulnerability was in good correlation with the peroxynitrite-evoked decrease of mitochondrial transmembrane potential (MTP) in astrocytes. A simultaneous exposure to glucose deprivation and SIN-1 rapidly depolarized MTP and depleted ATP in astrocytes. Inclusion of ciclopirox initially increased the MTP, maintained it high, and blocked the ATP depletion in glucose-deprived SIN-1-treated astrocytes. However, ciclopirox did not prevent the depletion of reduced glutathione in glucose-deprived SIN-1-treated astrocytes. Consistently, ciclopirox did not scavenge various kinds of oxidants including peroxynitrite, nitric oxide, superoxide anion, hydrogen peroxide and hydroxyl radical. Ciclopirox has been experimentally used as a cell cycle G1/S phase transition blocker (Hoffman et al., Cytometry 12 (1991) 26). Flow cytometry analysis, however, showed that the cytoprotective effect of ciclopirox was not attributed to its inhibition of the cell cycle progression. The present results indicate that ciclopirox protects astrocytes from peroxynitrite cytotoxicity by attenuating peroxynitrite-induced mitochondrial dysfunction.

Adenosine Triphosphate↗

PubMed1995

Thiamine deficiency in cultured neuroblastoma cells: effect on mitochondrial function and peripheral benzodiazepine receptors.

When neuroblastoma cells were transferred to a medium of low (6 nM) thiamine concentration, a 16-fold decrease in total intracellular thiamine content occurred within 8 days. Respiration and ATP levels were only slightly affected, but addition of a thiamine transport inhibitor (amprolium) decreased ATP content and increased lactate production. Oxygen consumption became low and insensitive to oligomycin and uncouplers. At least 25% of mitochondria were swollen and electron translucent. Cell mortality increased to 75% within 5 days. [3H]PK 11195, a specific ligand of peripheral benzodiazepine receptors (located in the outer mitochondrial membrane) binds to the cells with high affinity (KD = 1.4 +/- 0.2 nM). Thiamine deficiency leads to an increase in both Bmax and KD. Changes in binding parameters for peripheral benzodiazepine receptors may be related to structural or permeability changes in mitochondrial outer membranes. In addition to the high-affinity (nanomolar range) binding site for peripheral benzodiazepine ligands, there is a low-affinity (micromolar range) saturable binding for PK 11195. At micromolar concentrations, peripheral benzodiazepines inhibit thiamine uptake by the cells. Altogether, our results suggest that impairment of oxidative metabolism, followed by mitochondrial swelling and disorganization of cristae, is the main cause of cell mortality in severely thiamine-deficient neuroblastoma cells.

Adenosine Triphosphate↗

PubMed2003

A novel water-soluble and cell-permeable calpain inhibitor protects myocardial and mitochondrial function in postischemic reperfusion.

The effects of the novel calpain inhibitor A-705239 were studied in isolated perfused rabbit hearts subjected to 45 min of global ischemia, followed by 60 min of reperfusion. During 15 min of perfusion the inhibitor accumulated in myocardial tissue up to 16 times the concentration in the perfusate. Almost complete recovery and survival of heart function (90%) was seen with an inhibitor concentration of 10(-8) M in the perfusion fluid when the compound was administered prior to ischemia. Left ventricular pressure amplitude and coronary flow showed significantly higher values during reperfusion in the presence of the inhibitor. A-705239 significantly reduced the release of creatine kinase, from 166+/-49 U/l in untreated hearts to 44+/-10 U/l, and diminished the release of lactate dehydrogenase from 118+/-20 U/l in untreated hearts to 63+/-4 U/l. Mitochondrial dysfunction following ischemia and reperfusion was markedly attenuated by the inhibitor. Thus, the state 3 respiration rate only decreased to 4.2 in contrast to 2.6 nmol O2/(min x mg s.w.) in untreated hearts, reflecting a reduced damage of oxidative phosphorylation. Furthermore, in the presence of the inhibitor the inner mitochondrial membranes became less permeable as indicated by a smaller leak respiration. The excellent properties of A-705239 should make this compound a valuable tool for further pharmacological studies.

Adenosine Diphosphate↗

PubMed1995

[Idiopathic Parkinson disease and mitochondrial functions].

Work on the molecular mechanisms of MPTP neurotoxicity have inspired search into the function of mitochondria in idiopathic Parkinson's disease. All the studies show a decrease of 30 to 40% in the activity of the respiratory complex I in the mitochondria of the nigra substantia. This decreased activity is not found in other degenerative Parkinsonisms treated with L-Dopa and cannot be explained simply by age. It is not found in other tissues including muscles and platelets. The causal mechanism of this mitochondrial dysfunction is unknown but it is not related to a mutation in mitochondrial DNA.

Humans↗

PubMed2026

Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.

Cellular pathways for experimental discovery provide a comprehensive overview of sirtuin biology and its critical involvement in HIV-associated neurocognitive disorders (HAND) and related neurodegenerative diseases, highlighting the translational potential of sirtuin-targeted therapeutic strategies. As NAD+-dependent deacetylases and ADP-ribosyl transferases, sirtuins regulate diverse cellular processes, including stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, autophagy, oxidative stress responses, and genomic stability, all of which contribute to neuronal dysfunction and disease progression. This chapter focuses on key mammalian sirtuins, including SIRT1 and SIRT2, which are primarily localized within the nucleus and cytosol; mitochondrial sirtuins SIRT3, SIRT4, and SIRT5; and nuclear/nucleolar sirtuins SIRT6 and SIRT7. Here, a method with a detailed protocol to isolate compartment-specific sirtuin expression and activity was used: subcellular fractionation was performed using a subcellular fractionation kit to obtain cytosolic and nuclear fractions, while mitochondrial isolation was carried out using Tom20 antibody-conjugated magnetic microbeads. These approaches were applied to brain tissues from HIV-positive individuals, as well as to HIV-Tat-treated human microglial (HMC3) cells and astrocytes. This experimental framework enables accurate assessment of compartment-resolved sirtuin regulation in disease-relevant models. Collectively, the chapter highlights the protective roles of sirtuins in mitigating key pathogenic mechanisms underlying HAND and related neurodegenerative diseases. These findings support the emerging concept that sirtuins represent promising pharmacological targets for the development of novel therapeutic interventions in neurodegeneration and HIV-associated brain disorders.

Humans↗

PubMed2000

Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in mitochondrial functions and is independent of CD95 (APO-1/Fas).

We have previously shown that nitric oxide (NO) induces apoptosis in different human neoplastic lymphoid cells through caspase activation. Here we studied the NO-mediated apoptosis in human breast cancer cell lines derived from primary tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN) induced apoptosis in both cell lines which was completely abrogated after pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into the cytosol, an increase in the number of cells with low mitochondrial transmembrane potential and with high level of reactive oxygen species production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas) ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively expressed at the mRNA level and did not show any changes upon NO treatment in both breast cancer cell lines. The expression of the pro-apoptotic protein Bax and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20 cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation of the caspase cascade and subsequent apoptosis in human breast cancer cells required mitochondrial damage (in particular, cytochrome c release, disruption of mitochondrial transmembrane potential and generation of reactive oxygen species) but not the activation of the CD95/CD95L pathway.

Apoptosis↗

PubMed1994

Mitochondrial function during heavy exercise.

Maximal rates, coupling, and control of oxidative phosphorylation were studied in isolated skeletal muscle mitochondria from rat and rabbit. Mitochondria were incubated under various conditions of temperature, pH, and substrate availability. A 20% decrease in coupling (ADP/O) was observed at 43 degrees C as compared to 37 degrees C in rat mixed skeletal muscle mitochondria. Changes in pH from 7.00 to 6.20 affected neither coupling nor maximal (state 3) respiration rates. Changing the substrate supply from pyruvate to palmitoyl-carnitine (+ malate) did not alter ADP/O, but markedly degraded the energy state sustained at submaximal ATP turnover. Thus, carbohydrate depletion may be associated with inhibition of contractile function and the recruitment of less economical higher threshold motor units. State 3 respiration of mitochondria from rabbit Type IIb fibers oxidizing pyruvate+malate+alpha-glycerophosphate was 27% higher than that of mitochondria from Type I rabbit skeletal muscle. However, the ADP/O ratio in the Type IIb preparation was 18% lower. The experimental findings suggest that temperature, substrate supply, and energetic differences between slow twitch and fast twitch motor units may impact the economy of mitochondrial oxygen utilization during heavy aerobic exercise, and thus contribute to the slow component of oxygen uptake.

Animals↗

PubMed1987

The effect of treatment with coenzyme Q10 on the mitochondrial function and superoxide radical formation in cardiac muscle hypertrophied by mild aortic stenosis.

A 40% reduction of the diameter of the ascending aorta maintained for 60 days induced the formation of a compensate cardiac hypertrophy in rabbits without changing the value of the azide insensitive Ca2+-ATPase activity in comparison to control hearts. The cardiac mitochondria isolated from constricted animals assayed in presence of glutamate and succinate did not show a change in the R.C.I. and ADP/O values in comparison to the controls, whilst the QO2 value enhanced or decreased respectively when determined with glutamate or succinate. The intramuscular injections of CoQ10 (12 mg/kg body weight/48 h) enhanced the mitochondrial CoQ10 concentrations both in the control and in the constricted animals and further increased the QO2 value determined in both groups of animals when glutamate was used as the substrate. The production of O2.- radicals by the level of the complexes I and III of the respiratory chain, did not change in the constricted animals, nor in the animals administered with CoQ10 in comparison to the control. CoQ10 augmented the rate of oxygen consumption by the submitochondrial particles only in the constricted animals. Moreover, the treatment with the coenzyme or the constriction of the aorta, did not modify the cardiac superoxide dismutase activity, but increased the glutathione peroxidase activity only in the banded animals. In addition, in the CoQ10 treated animals there was a reduction of NADH-diaphorase activity both in the control and constricted animals, while the malondialdehyde, generated during the thiobarbituric acid test, and the cardiac content of lipofuscin were decreased.

Animals↗

PubMed2002

Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice.

The mdx mouse serves as animal model for Duchenne muscular dystrophy. Energy status in muscles of mdx mice is impaired and we have demonstrated recently that the energy precursor creatine exerts beneficial effects on mdx skeletal muscle cells in culture. Here we show that feeding a creatine-enriched diet to new-born mdx mice strongly reduced the first wave of muscle necrosis four weeks after birth. Necrosis of the fast-twitch muscle extensor digitorum longus was inhibited by 63+/-14% (P<0.0001) while necrosis of the slow-twitch soleus muscle was not significantly decreased. In addition, using chemically skinned muscle fibres, we found that mitochondrial respiration capacity was decreased by about 25% in mdx-derived fibres and that long-term creatine-feeding restored respiration to wild-type levels. These results provide evidence that creatine supplementation in mdx mice improves muscle health and may provide a scientific basis for its use as adjuvant therapy in Duchenne muscular dystrophy.

Animals↗

PubMed1995

Approaches that mitigate doxorubicin-induced delayed adverse effects on mitochondrial function in rat hearts; liposome-encapsulated doxorubicin or combination therapy with antioxidant.

This experiment was designed to evaluate whether or not liposomal encapsulated-doxorubicin and combination therapy of free doxorubicin with coenzyme Q10, an antioxidant, mitigate the delayed adverse effects on cardiac muscle mitochondria. Rats aged 7 weeks were divided into the following four groups; rats were injected with doxorubicin or liposomal encapsulated-doxorubicin, total dose 15 mg/kg. The doxorubicin group consisted of two subgroups depending on diet, i.e., standard diet or 0.2% coenzyme Q10 diet. Mitochondria from cardiac muscles were prepared from rats aged 13 and 35 weeks. No significant decrease in the activity of complex I of the mitochondrial electron transport chain was observed in rats aged 13 weeks among the groups, however, significant decreases in the activity in rats aged 35 weeks were observed in the doxorubicin and liposomal doxorubicin groups compared with the corresponding control rats. In contrast, no significant change in complex I activity was observed in rats fed with coenzyme Q10 diet irrespective of doxorubicin treatment. From these results, not liposomal encapsulation of doxorubicin but combination therapy with antioxidant might be expected to reduce the delayed adverse effects of doxorubicin on heart mitochondria.

Animals↗

PubMed2005

Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes.

INTRODUCTION: Obese and type 2 diabetic (T2DM) adolescents present with reduced insulin-stimulated glucose disposal and elevated intramyocellular lipids (IMCL) indicating comparable muscular insulin resistance and increased flux of free fatty acids (FFA) as in adult patients. In humans, the causal relationships between obesity and insulin resistance were examined in detail over the last years. METHODS: The impact of genetic factors was analyzed in young nonobese nondiabetic first-degree relatives of T2DM (REL-DM), whereas environmental factors were tested by challenging humans without genetic T2DM risk with lipid infusions or high-fat diets. RESULTS: REL-DM exhibit defects in mitochondrial oxidation and phosphorylation. Increased FFA availability results in accumulation of intramyocellular fatty acyl-CoA (FA-CoA) inducing a series of alterations: (i) inhibition of insulin signaling, (ii) reduction of insulin-(in)dependent glucose transport/phosphorylation, (iii) decreased insulin-stimulated glycogen synthesis, (iv) impaired insulin-stimulated oxidative phosphorylation (ATP synthesis), (v) accumulation of ectopic triglycerides (IMCL), (vi) reduced expression of peroxisome proliferator activated receptor gamma (PPARgamma) coactivator-1 (PGC-1) and PGC-1-controlled genes involved in mitochondrial biogenesis and oxidative phosphorylation and possibly also (vii) initiation of inflammatory processes by activation of PKC and nuclear factor-kappaB and decreased expression of matrix metalloproteinases (MMPs). CONCLUSIONS: The abnormalities could lead to a vicious cycle in which mitochondrial dysfunction, elevation of intramycellular lipids, impaired lipid oxidation and insulin resistance amplify each other. This is similar to the adaptive changes to fasting, which prevent energy loss during excessive FFA availability. The sequence of events may start with mitochondrial dysfunction in genetic insulin resistance and with increased intramyocellular lipids in environmental insulin resistance.

Adolescent↗

PubMed2004

Mitochondrial function in apoptotic neuronal cell death.

Apoptosis can be defined as the regulated death of a cell and is conducted by conserved pathways. Apoptosis of neurons after injury or disease differs from programed cell death, in the sense that neurons in an adult brain are not "meant" to die and results in a loss of function. Thus apoptosis is an honorable process by a neuron, a cell with limited potential to replace itself, choosing instead to commit suicide to save neighboring cells from release of cellular components that cause injury directly or trigger secondary injury resulting from inflammatory reactions. The excess of apoptosis of neuronal cells underlies the progressive loss of neuronal populations in neurodegenerative disorders and thus is harmful. Mitochondria are the primary source for energy in neurons but are also poised, through the "mitochondrial apoptosis pathway," to signal the demise of cells. This duplicity of mitochondria is discussed, with particular attention given to the specialized case of pathological neuronal cell death.

Animals↗

PubMed1996

Calcineurin and mitochondrial function in glutamate-induced neuronal cell death.

We have previously reported that glutamate can trigger a succession of necrosis and apoptosis in cerebellar granule cells (CGC). Since specific blockers of the N-methyl-D-aspartate (NMDA) receptor channel prevented both types of cell death, the role of Ca2+-dependent processes in the initiation of glutamate toxicity was further investigated. We examined the possible involvement of mitochondria and the role of the Ca2+/calmodulin-regulated protein phosphatase, calcineurin, in the development of either type of cell death. Cyclosporin A and the more selective calcineurin inhibitor, FK-506, prevented the development of both early necrosis and delayed apoptosis. In addition, cyclosporin A prevented the collapse of mitochondrial membrane potential observed during the exposure to glutamate and the concomitant necrotic phase. When CsA was added immediately after glutamate removal, it also prevented delayed apoptosis of neurons that had survived the necrotic phase. Altogether, these results suggest the involvement of calcineurin and a role for mitochondrial deenergization as early signals in neuronal apoptosis induced by glutamate.

Animals↗

PubMedDate not supplied

[Changes in mitochondrial function in the cells and cytoplasts of a pig embryo kidney culture as affected by the action of actinomycin D].

Vital staining of PE kidney cells by fluorescent cationic dye, ethyl rhodamine, (accumulated inside mitochondria by the membrane potential and hence reflecting their functional state) shows rather close level of the fluorescence intensity both in cells and in their cytoplasts for 10 hours of culture survival in the standard medium. In cells and cytoplasts cultivated in the medium with 0.2 mg/ml of actinomycin D inhibiting RNA synthesis, fluorescence intensity of mitochondria sharply decreases after 10 hours as against the control patterns. It is concluded that mitochondria possess a significant degree of autonomy of the nucleus and it is supposed that a considerable part of mitochondrial RNA is under the nucleus control.

Animals↗

PubMed2004

Mitochondrial histone-like DNA-binding proteins are essential for normal cell growth and mitochondrial function in Crithidia fasciculata.

The Crithidia fasciculata KAP2 and KAP3 proteins are closely related kinetoplast-specific histone-like DNA-binding proteins. The KAP2 and KAP3 genes are 46% identical and are arranged in tandem on the chromosomal DNA. Disruption of both alleles of either gene alone shows no detectable phenotype. However, replacement of both copies of the sequence encoding the entire KAP2 and KAP3 locus increases maxicircle mRNA levels two- to fourfold. These double-knockout cells are viable but grow extremely slowly, have reduced respiration and very abnormal cell morphologies, and accumulate numerous large vacuoles. The extreme phenotype of these mutant cells suggests an important role for the KAP2 and KAP3 proteins in mitochondrial metabolism and cell growth.

Animals↗

PubMed2004

Modeling mitochondrial function in aging neurons.

Mitochondria and aging are fast becoming two of the most paired terms in biology. As a crucial nexus for the cell, mitochondria are involved in numerous essential aspects of cell function, from energy production via the respiratory chain to steroid biosynthesis, heme assembly, pyrimidine biosynthesis, the tricarboxylic acid cycle, and apoptosis. Mitochondria are also the main producers of reactive oxygen species within the cell. Theories about aging have revolved around mitochondria for decades, but it is only in the past few years that animal models have started to give significant insights into mitochondria-mediated pathophysiology that might be intimately associated with aging. This review will highlight several new animal models of mitochondrial dysfunction in the context of aging.

Aging↗

PubMed1984

Rat liver mitochondria prepared in mannitol media demonstrate increased mitochondrial volumes compared with mitochondria prepared in sucrose media. Relationship to the effect of glucagon on mitochondrial function.

Liver mitochondria isolated from glucagon-treated rats by using both mannitol- and sucrose-based media showed enhanced uncoupled succinate oxidation, pyruvate metabolism and citrulline synthesis. Mitochondria prepared in mannitol medium showed some stimulation of these parameters compared with those prepared in sucrose medium. This was accompanied by an increase in matrix volume of about 20%. Some [14C]mannitol became permanently associated with mitochondria during preparation. It is suggested that mannitol may enter mitochondria during their preparation and cause swelling. The presence of 4mM-phosphate in the sucrose isolation medium stimulated the same parameters as did glucagon treatment, and also caused an increase in matrix volume of about 20%. These results confirm the conclusion that the mitochondrial volume may be important in the regulation of mitochondrial metabolism. They contradict the conclusion of others [Siess (1983) Hoppe-Seyler's Z. Physiol. Chem. 364, 279-290, 835-838] that mannitol rather than sucrose should be used when studying hormonal effects on mitochondrial metabolism. Reasons for the discrepancies in the results between groups studying the effects of hormones on mitochondrial metabolism are discussed.

Animals↗

PubMedDate not supplied

In vivo assessment of mitochondrial functionality in human gastrocnemius muscle by 31P MRS. The role of pH in the evaluation of phosphocreatine and inorganic phosphate recoveries from exercise.

In this study we compared the kinetics of phosphocreatine (PCr) and P(i) recovery, and their dependency on cytosolic pH in 38 normal individuals. Spectra were acquired during rest, work and recovery. A time resolution of 10 s was used to obtain detailed information. The kinetics of PCr and P(i) recovery almost overlapped when the lowest value of cytosolic pH reached during recovery (termed the minimum pH) was < 6.95, while they were completely dissociated when the minimum pH was > 6.95. This result is interpreted as indirect in vivo evidence of the kinetic control exerted by ADP on mitochondrial oxidation. Our results represent a rationale for new experimental conditions to be used in clinical routine studies of pathologies due to primary or secondary mitochondrial malfunction.

Adult↗