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PubMed2005

Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency.

X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMed2001

Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus.

Ischemic tolerance in brain develops when sublethal ischemic insults occur before "lethal" cerebral ischemia. Two windows for the induction of tolerance by ischemic preconditioning (IPC) have been proposed: one that occurs within 1 hour after IPC, and another that occurs 1 or 2 days after IPC. The authors tested the hypotheses that IPC would reduce or prevent ischemia-induced mitochondrial dysfunction. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mm Hg) for 2 and 10 minutes, respectively. Nonsynaptosomal mitochondria were harvested 24 hours after the 10-minute "test" ischemic insult. No significant changes were observed in the oxygen consumption rates and activities for hippocampal mitochondrial complexes I to IV between the IPC and sham groups. Twenty-four hours of reperfusion after 10 minutes of global ischemia (without IPC) promoted significant decreases in the oxygen consumption rates in presence of substrates for complexes I and II compared with the IPC and sham groups. These data suggest that IPC protects the integrity of mitochondrial oxidative phosphorylation after cerebral ischemia.

Animals↗

PubMed2005

Identification of a functioning mitochondrial uncoupling protein 1 in thymus.

We present evidence that rat and mouse thymi contain mitochondrial uncoupling protein (UCP 1). Reverse transcriptase-PCR detected RNA transcripts for UCP 1 in whole thymus and in thymocytes. Furthermore, using antibodies to UCP 1 the protein was also detected in mitochondria isolated from whole thymus and thymocytes but not in thymus mitochondria from UCP 1 knock-out mice. Evidence for functional UCP 1 in thymus mitochondria was obtained by a comparative analysis with the kinetics of GDP binding in mitochondria from brown adipose tissue. Both tissues showed equivalent B(max) and K(D) values. In addition, a large component of the nonphosphorylating oxygen consumption by thymus mitochondria was inhibited by GDP and subsequently stimulated by addition of nanomolar concentrations of palmitate. UCP 1 was purified from thymus mitochondria by hydroxyapatite chromatography. The isolated protein was identified by peptide mass mapping and tandem mass spectrometry by using MALDI-TOF and LC-MS/MS, respectively. We conclude that the thymus contains a functioning UCP 1 that has the capacity to regulate metabolic flux and production of reactive oxygen-containing molecules in the thymus.

Amino Acid Sequence↗

PubMed1981

Effects of chronic emetine treatment on mitochondrial function.

Emetine has long been recognized as a cardiotoxic drug, but its mechanism remains unknown. Since many studies reported an effect of emetine on cardiac metabolism, permanent damage to the heart could result from such treatment. To investigate this action of emetine in relation to the cardiotoxicity seen after a therapeutic regimen, New Zealand albino rabbits were given 2 mg/kg/day ip of emetine for 9 days. Heart and liver mitochondrial metabolism was assessed polarographically using pyruvate, pyruvate plus malate, or succinate as the substrate. Heart mitochondrial metabolism was reduced in emetine-treated rabbits in comparison to the normal controls. However, the metabolic activity of the pair-fed control group was equally reduced. Only the liver mitochondrial metabolism of the pair-fed control group was reduced in relation to the normal controls, while the liver mitochondrial metabolism of emetine-treated rabbits remained unchanged. These data indicated that the reduction in heart mitochondrial metabolism resulted from the inanition induced by the chronic emetine treatment and not from a primary effect of the drug.

Animals↗

PubMed1998

In vitro toxicity of surfactants in U937 cells: cell membrane integrity and mitochondrial function.

Surface-active agents are components of many drugs and cosmetics. In order to examine their cytotoxic and membrane-toxic potential, various surfactants were examined in U937 cells using the tetrazolium reduction assay EZ4U, a modified XTT test, and the arachidonic acid release test (AART). EZ4U measures the ability of living cells to reduce a colorless tetrazolium salt to an orange water-soluble formazan derivative by mitochondrial dehydrogenases. [3H]arachidonic acid ([3H]AA) is rapidly incorporated into cell membrane phospholipids. Due to membrane disintegration or enzymatic catalysis, it is released into the cell culture medium and can be measured by scintillation technique. The results after 24-hour-exposure are as follow (CC50 microg/ml; RC50 microg/ml): benzalkonium chloride (0.6), Cremophor A25 (1.4; 5.9), sodium cetearyl sulfate (1.6; 19.9), Brij78 (1.6; 7.7), TEGO betaine E (3.0; 19.3), TEGO betaine CKD (4.1; 20.2), TEGO betaine L7 (7.5; 20.0), sodium dodecyl sulfate (7.5; 39.0), Triton X-100 (8.9; 110), polysorbate 80 (48.1; 491), soybean lecithin (7920; 19940).

Arachidonic Acid↗

PubMed1991

Protection of cellular and mitochondrial functions against anoxic damage by fructose in perfused liver.

In anoxic perfused liver, conversion of fructose to lactate was greatly increased to about 3 mumol/min per g liver. This increase in lactate implied that the same amount of ATP was also produced. The rate of metabolism of glucose was less than 10% of that of fructose, as judged by rate of production of lactate. In anoxic liver perfused with fructose, the ATP levels of both the tissue and mitochondria remained high, despite lack of oxygen, thus preventing enzyme leakage and preserving processes requiring ATP, such as bile excretion and urea formation. The mitochondrial oxidative phosphorylation capacity of anoxic liver perfused with fructose was also unimpaired. Spectral analysis of light transmitted through the liver revealed that the mitochondrial electron transfer system was in the completely reduced state during anoxia, indicating that the mitochondria were incapable of synthesizing ATP. These results suggest that fructose metabolism during anoxia resulted in sufficient production of ATP for maintaining the physiological functions of the cells and the oxidative phosphorylation capacity of their mitochondria.

Adenine Nucleotides↗

PubMed2005

Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function.

Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl-beta-cyclodextrin can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.

Adenosine Triphosphate↗

PubMed2005

Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle.

Severe high-altitude hypoxia exposure is considered a triggering stimulus for redox disturbances at distinct levels of cellular organization. The effect of an in vivo acute and severe hypobaric hypoxic insult (48 h at a pressure equivalent to 8,500 m) on oxidative damage and respiratory function was analyzed in skeletal muscle mitochondria isolated from vitamin E-supplemented (60 mg/kg ip, 3 times/wk for 3 wk) and nonsupplemented mice. Forty male mice were randomly divided into four groups: control + placebo, hypoxia + placebo (H + P), control + vitamin E, and hypoxia + vitamin E. Significant increases in mitochondrial heat shock protein 60 expression and protein carbonyls group levels and decreases in aconitase activity and sulfhydryl group content were found in the H + P group when compared with the control + placebo group. Mitochondrial respiration was significantly impaired in animals from the H + P group, as demonstrated by decreased state 3 respiratory control ratio and ADP-to-oxygen ratio and by increased state 4 with both complex I- and II-linked substrates. Using malate + pyruvate as substrates, hypoxia decreased the respiratory rate in the presence of carbonyl cyanide m-chlorophenylhydrazone and also stimulated oligomycin-inhibited respiration. However, vitamin E treatment attenuated the effect of hypoxia on the mitochondrial levels of heat shock protein 60 and markers of oxidative stress. Vitamin E was also able to prevent most mitochondrial alterations induced by hypobaric hypoxia. In conclusion, hypobaric hypoxia increases mitochondrial oxidative stress while decreasing mitochondrial capacity for oxidative phosphorylation. Vitamin E was an effective preventive agent, which further supports the oxidative character of mitochondrial dysfunction induced by hypoxia.

Acute Disease↗

PubMed1975

Mitochondrial function and excitation-contraction coupling in the development of alcoholic cardiomyopathy.

The effect of prolonged adminstration of ehtanol on cardiac metabolism, contractility, and ultrastructure was investigated. Dogs received 400 ml of a 25 percent solution of ethanol during a period of 3-6 months. Repeated heart muscle biopsied revealed a significant diminution in the activity of intramitochondrial NAD-linked isocitrate dehydrogenase in the animals exposed to alcohol. Oxidative, phosphorylation of mitochondria was measured polarographically using a vibrating oxygen electrode; respiratory control index and mitochondrial oxygen consumption were markedly reduced (p less than 0.001). Myocardial ATP content was significantly diminished (p less than 0.025). Electron microscopic changes observed consisted of mitochondrial degeneration, dehiscence of intercalated discs, and dilatation of intercellular spaces. The average force velocity curve was shifted downward and to the left in afterloaded contractions with a significant depression of Vmax (p less than 0.01). Both calcium binding and calcium uptake of mitochondria and sarcoplasmic reticulum were inhibited. These results suggest that a disorder in the generation of energy and a defect in calcium binding by subcellular membranes may be the determinant events leading to impaired myocardial function in the course of chronic alcoholism.

Adenine Nucleotides↗

PubMed2000

Functional mitochondrial heterogeneity in heteroplasmic cells carrying the mitochondrial DNA mutation associated with the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes).

Most mitochondrial DNA (mtDNA) alterations associated with human disorders are heteroplasmic, i.e. mutant mtDNA molecules coexist with normal ones within the cell. We addressed the possibility of intermitochondrial exchanges through histologic analyses of cybrid clones with increasing proportion of the MELAS (A3243G) mtDNA transfer RNA point mutation. MtDNA-dependent cytochrome c oxidase activity and protein composition as well as mitochondrial membrane potential appeared heterogeneous in individual cells from clonal heteroplasmic cell populations on the basis of confocal and electron microscopy. The number of defective cells increased with increasing mutation load. We conclude that in the presence of a heteroplasmic mtDNA mutation in the cell type that we studied, intermitochondrial molecular exchanges cannot provide an efficient even distribution of the complementing molecules such as wild-type mtDNA, transfer RNA, or protein. Mitochondria in these heteroplasmic cells cannot, therefore, be considered a single functional unit.

Cell Fusion↗

PubMed2002

Diversity in mitochondrial function explains differences in vascular oxygen sensing.

Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O2 tension is detected by an unidentified redox sensor, which controls K+ channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O2 sensors. Mitochondria-derived activated oxygen species (AOS), like H2O2, can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K+ channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K+ current and constrict PAs while increasing AOS production and outward K+ current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H2O2 production. Similarly, production of AOS and H2O2 is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H2O2, can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.

Animals↗

PubMed1994

Yta10p, a member of a novel ATPase family in yeast, is essential for mitochondrial function.

The yeast gene, YTA10, encodes a member of a novel family of putative ATPases. Yta10p, as deduced from the nucleotide sequence, is 761 amino acids in length (predicted molecular mass 84.5 kDa). The amino acid sequence of Yta10p exhibits high similarity to two other yeast proteins, Yta11 and Yta12, and to E. coli FtsH. Several features of Yta10p are compatible with its localization in mitochondria. We report here that Yta10p is a yeast mitochondrial protein and that import is dependent on a membrane potential and accompanied by processing to a protein of approximately 73 kDa. Disruption of YTA10 leads to a nuclear petite phenotype and to a loss of respiratory competence, as shown by spectrophotometric measurement of the activities of respiratory complexes I-III and IV, respectively. These findings together with the high similarity of Yta10p to several ATP-dependent proteases suggest that Yta10p is a mitochondrial component involved, directly or indirectly, in the correct assembly and/or maintenance of active respiratory complexes.

Adenosine Triphosphatases↗

PubMed2005

Effects of 6-hydroxydopamine on mitochondrial function and glutathione status in SH-SY5Y human neuroblastoma cells.

SH-SY5Y human neuroblastoma cells were incubated with 6-hydroxydopamine (6-OHDA) for 4 and 24 h to examine the mechanism of cell death and to determine the time-dependent effects of 6-OHDA on cellular glutathione status. After 4 h, 6-OHDA significantly depleted cellular ATP and GSH concentrations with only slight increases in cell death. GSH:GSSG ratios and mitochondrial membrane potential (Deltapsim) were significantly decreased during 4 h incubations with 6-OHDA. High concentrations of 6-OHDA (100 microM) induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells within 4 h leading to cell death. In 24 h incubations, 25 and 50 microM 6-OHDA significantly decreased ATP concentrations; however, significant increases in cell death were only observed with 50 microM 6-OHDA. 6-OHDA induced a concentration-dependent increase in GSH and total glutathione concentrations after 24 h. After exposure to 50 microM 6-OHDA, GSH concentrations were increased up to 12-fold after 24 h with no change in the GSH:GSSG ratio. Gene analysis suggests that the increase in GSH concentration was due to increased expression of the GSH synthesis genes glutamate cysteine ligase modifier and catalytic subunits. Our results suggest that 6-OHDA induces oxidative stress in SH-SY5Y cells resulting in an adaptive increase in cellular GSH concentrations.

Adenosine Triphosphate↗

PubMedDate not supplied

Modulation of intracellular calcium signaling and mitochondrial function in cultured osteoblastic cells by dexamethasone and celecoxib during mechanical stimulation.

OBJECTIVE: Evaluation of potentially therapeutically relevant effects of dexamethasone and celecoxib on crucial parameters of bone physiology during and following mechanical stimulation in cultured osteoblasts. METHODS: An in vitro mechanical stimulation model based on the rat osteogenic cell line UMR-106 was developed to investigate glucocorticoid (dexamethasone) and selective COX-2 inhibitor (celecoxib) induced changes in the intracellular calcium concentration ([Ca2+]i) and mitochondrial membrane potential (deltapsi(m)). Microfluorometric techniques were applied to monitor [Ca2+]i (Fura-2 AM) and deltapsi(m) (rhodamine 123) online as the main parameters of the actual cellular metabolism. RESULTS: Basal [Ca2+] was found to be 92.2 +/- 3.7 nM and increased tip to 711 +/- 27 nM during mechanical stimulation under controlled conditions. Addition of 100 nM dexamethasone or 10 microM celecoxib for 24 h suppressed the increase in [Ca2+]i significantly to 530 +/- 33 nM and 546 +/- 39 nM, respectively. Dexamethasone significantly reduced, but celecoxib significantly increased the spread velocity of the mechanically induced intracellular calcium wave. Furthermore, the effects induced by dexamethasone were amplified during the inhibition of gap junction coupling and diminished following enlarged gap junction coupling. In contrast, the modulation of gap junction coupling exerted only a minor influence on the celecoxib-induced effects. Short-term application of dexamethasone (5 min) caused significantly reduced mechanically induced depolarization of the mitochondrial membrane, but long-term application (24 h) did not. In contrast, only the long-term application (24 h) of celecoxib caused such depolarization. CONCLUSION: The observed effects of dexamethasone and celecoxib on mechanically induced changes in [Ca2+] and deltapsi(m) are suggested to result from short-term changes in membrane characteristics and long-term changes in protein synthesis. This indicates an influence of these drugs on cell-to-cell communication and metabolism that may be therapeutically relevant.

Animals↗

PubMed2001

[In vitro protection of cerebral mitochondrial function by E-resveratrol in anoxia followed by re-oxygenation].

Using an experimental model of anoxia-reoxygenation applied to suspensions of mitochondria isolated from rat cortex, we have searched the effects of resveratrol added to the suspension or previously injected to rats from which mitochondria were extracted. With this model, we observe that resveratrol counteracts decoupling effects induced by anoxia-reoxygenation. It also fully inhibits intermembrane cytochrome c release, initial step of mitochondrial apoptosis and blocks ATP generation which achieves it. These effects are concentration-dependent and take place at low concentrations. It is concluded that resveratrol limits or suppresses the mitochondrial deleterious effects promoted by anoxia followed by reoxygenation.

Adenosine Triphosphate↗

PubMed2001

Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain.

Hypoxia-inducible factor (HIF) mediates a large number of transcriptional responses to hypoxia and has an important role in processes that include angiogenesis and erythropoiesis. The HIF DNA binding complex consists of 2 basic-helix-loop-helix PAS proteins designated alpha and beta subunits. Regulation occurs principally through the alpha subunits, which are stabilized and activated in hypoxia. Although substantial evidence implicates reactive oxygen species (ROS) in the regulatory process, the precise mechanisms remain unclear. Mitochondria are an important source of ROS, and in one model it has been proposed that hypoxia increases the generation of ROS at complex III in the mitochondrion and that this signal acts through a transduction pathway to stabilize HIF-1alpha and to activate HIF. To test this model the induction of the HIF-1alpha subunit and the HIF target gene, glucose-transporter-1, was examined in a variety of mutant cells that lacked mitochondrial DNA (rho0) or had other genetic defects in mitochondrial respiration. HIF induction by hypoxia was essentially normal in all cells tested. Hydrogen peroxide production was measured by the luminol/peroxidase method and found to be reduced in rho0 versus wild-type cells and reduced by hypoxia in both rho0 and wild-type cells. Furthermore, concentrations of rotenone that maximally inhibited respiration did not affect HIF activation by hypoxia. These data do not support the model outlined above and indicate that a functional respiratory chain is not necessary for the regulation of HIF by oxygen.

Animals↗

PubMed2000

In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid beta-peptide and iron: evidence for a stress response.

Mild metabolic stress can increase resistance of neurons in the brain to subsequent more severe insults, as exemplified by the beneficial effects of heat shock and ischemic preconditioning. Studies of Alzheimer's disease and other age-related neurodegenerative disorders indicate that dysfunction and degeneration of synapses occur early in the cell death process, and that oxidative stress and mitochondrial dysfunction are central events in this pathological process. It was recently shown that administration of 2-deoxy-d-glucose (2DG), a nonmetabolizable glucose analog that induces metabolic stress, to rats and mice can increase resistance of neurons in the brain to excitotoxic, ischemic, and oxidative injury. We now report that administration of 2DG to adult rats (daily i.p. injections of 100 mg/kg body weight) increases resistance of synaptic terminals to dysfunction and degeneration induced by amyloid beta-peptide and ferrous iron, an oxidative insult. The magnitude of impairment of glucose and glutamate transport induced by amyloid beta-peptide and iron was significantly reduced in cortical synaptosomes from 2DG-treated rats compared to saline-treated control rats. Mitochondrial dysfunction, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated after exposure to amyloid beta-peptide and iron in synaptosomes from 2DG-treated rats. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from 2DG-treated rats, suggesting a mechanism whereby 2DG protects synaptic terminals. We conclude that 2DG bolsters cytoprotective mechanisms within synaptic terminals, suggesting novel preventative and therapeutic approaches for neurodegenerative disorders.

ATP-Binding Cassette Transporters↗

PubMed1975

Studies on a temperature sensitive nuclear petite mutant of Saccharomyces cerevisiae: phenotypic reversibility of the mitochondrial functions.

1. We have studied the pleiotropic effect of a single-gene mutation of the pts mutant strain 1511 grown at 23 degrees C and 36 degrees C. 2. Growth of the mutant at the non-permissive temperature results in a decrease of respiration rate to about 50% after one generation and to less than 5% after five generations. The cytochrome spectra analysis revealed that only cytochrome c was present after growth at 36 degrees C. 3. Mitochondrial protein synthesis experiments in vivo demonstrated that the protein synthesizing system was not as rapidly inactivated by high temperature as the respiratory system. 4. The recovery of the respiratory capacity of the cells at 23 degrees C is complete but dependent on the de novo synthesis of a temperature sensitive protein.

Cell Nucleus↗