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PubMed2006

Mitochondrial functions and estrogen receptor-dependent nuclear translocation of pleiotropic human prohibitin 2.

Proteins with multiple cellular functions provide biological diversity to eukaryotic cells. In the current studies, we identified the mitochondrial functions of human prohibitin 2 (PHB2), which was initially identified as a repressor of estrogen-dependent transcriptional activity. The mitochondrial complex of PHB2 consists of PHB1, voltage-dependent anion channel 2, adenine nucleotide translocator 2, and the anti-apoptotic Hax-1, which is a novel binding partner for PHB2. RNA interference-mediated knockdown of PHB2 in HeLa cells resulted in caspase-dependent apoptosis through down-regulation of Hax-1 and fragmentation of mitochondria. We also found that, although PHB2 is predominantly expressed in the mitochondria of HeLa cells, it translocates to nucleus in the presence of estrogen receptor alpha and estradiol. Here, we first demonstrated the roles of mammalian PHB2 in mitochondria and the molecular mechanism of its nuclear targeting and showed that PHB2 is a possible molecule directly coupling nuclear-mitochondrial interaction.

Active Transport, Cell Nucleus↗

PubMed1991

Creatine kinase and mechanical and mitochondrial functions in hereditary and diabetic cardiomyopathies.

To determine whether the development of cardiomyopathies is associated with alterations in creatine kinase function, the functional properties of cardiac contractile apparatus and mitochondria were studied in two different models of cardiomyopathies, the Syrian hamster (hereditary dilated cardiomyopathy, strain UM-X7.1, 200 days old) and the diabetic rat (4-6 weeks after injection of streptozotocin) using ventricular skinned fibers. After Triton X-100 treatment, the hereditary cardiomyopathic fibers demonstrated decreased maximal calcium-activated tension and unchanged calcium sensitivity, whereas fibers from diabetic hearts exhibited unchanged maximal tension and increased calcium sensitivity, when compared with their respective controls. In both cases myofibrillar creatine kinase appeared unchanged. The functional properties of total tissue mitochondria were evaluated using saponin-skinned fibers. Coupling between oxidation and phosphorylation was not altered in cardiomyopathies. Respiration rate (per unit of tissue dry weight) was normal in hereditary cardiomyopathy but was considerably lower in diabetic fibers compared with control fibers. In both models of cardiomyopathies, creatine-stimulated respiration was significantly lower than in controls, thus indicating the depression of functional activity of mitochondrial creatine kinase.

Animals↗

PubMed2007

Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome.

The Parkinsonian syndrome induced by pesticides is associated with the impairment of mitochondrial function. Toxicants that inhibit selectively NADH-dehydrogenase activity, as rotenone or pyridaben, also show a selective inhibition of O2 uptake and respiratory control in rat brain mitochondria in the presence of NAD-dependent substrates. The IC50 of rotenone and pyridaben for complex I inhibition were in the range 1.7-2.2 microM. The determination of NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome oxidase activities in rat brain submitochondrial showed again the selective inhibition of Complex I by rotenone and pyridaben, whereas paraquat produced a non-selective inhibition affecting all the respiratory chain complexes. In rat brain mitochondria, rotenone and pyridaben markedly decreased mtNOS functional activity with NAD-dependent substrates but not when the substrate was succinate. This observation suggest than mtNOS activity is regulated by the activity of complex I. This regulation and the role of mitochondrial NO diffusion as a signal for mitochondrial biogenesis could have a role in the etiopathology of Parkinson's disease.

Animals↗

PubMed1980

Mitochondrial function of rat liver in biliary obstruction.

An investigation was performed of the liver mitochondrial respiratory function in rats after 1, 3 and 6 weeks of biliary obstruction and the following results were obtained: 1) Various parameters of liver mitochondrial respiratory function, such as respiratory control ratio, ADP/O, O2 consumption in state 3 respiration and adenosine triphosphate synthesis were found to decrease with prolongation of biliary obstruction. 2) The mitochondrial respiratory enzymes, cytochrome a (+a3) and cytochrome c(+c1) showed that both decreased in contents with prolongation of obstruction, particularly the latter. 3) The activation ratio of ATPase (latent ATPase/dinitrophenol stimulated ATPase) was increased after long term biliary obstruction, which was thought to indicate the severe damage of mitochondrial membrane. 4) Investigation of the respiratory function with the various respiratory substrates showed that the locations of mitochondrial respiratory inhibition in obstructive jaundice are at sites 1 and 2, which is the same as the situation seen in nonspecific damage of mitochondria. 5) There was a high degree of mitochondrial respiratory disturbance by bile acids, particularly CDCA, which is thought to be one of the causal factors of liver dysfunction in obstructive jaundice. 6) Mitochondrial respiratory function was markedly disturbed in hypotension, and the degree of which correlated with length of time of biliary obstruction.

Adenosine Triphosphatases↗

PubMed1997

Mitochondrial function in oncogene-transfected rat fibroblasts isolated from multicellular spheroids.

Two mitochondrion-specific fluorochromes, 10-N-nonyl acridine orange (NAO) and rhodamine 123 (Rh123), were used to determine the mechanism responsible for alterations in energy metabolism of transformed rat embryo fibroblast cells isolated from different locations within multicellular spheroids. Accumulation of Rh123 depends on intact mitochondrial membrane potential, whereas NAO is taken up by mitochondria independently of their function and thus represents mitochondrial distribution only. A reproducible selective dissociation procedure was used to isolate cells from different locations within the spheroids. After isolation, cells were simultaneously stained with one mitochondrial stain and the DNA dye Hoechst 33342, and several parameters, including cell volume, were monitored via multilaser-multiparameter flow cytometry. Our data clearly show a decrease in the uptake of Rh123 in cells from the periphery to the inner regions of the tumor spheroids, reflecting a persistent alteration in mitochondrial function. However, NAO staining experiments showed no reduction in the total mitochondrial mass per unit cell volume. Because cells were exposed to stain under uniform conditions after isolation from the spheroid, these data indicate the downregulation of mitochondrial function is associated with cell quiescence rather than a transient effect of reduced nutrient availability. This result, which is in accordance with data from two other cell lines (EMT6 and 9L), might reflect a general phenomenon in multicellular spheroids, supporting the hypothesis that quiescent cells in the innermost viable spheroid layer stably reduce their mitochondrial function, presumably to compensate for lower nutrient supply and/or decreased energy demand.

Acridine Orange↗

PubMed2000

Spermatozoal methylene blue reduction: an indicator of mitochondrial function and its correlation with motility.

Methylene blue reduction rates (MeBRR) were evaluated spectrophotometrically to study bovine spermatozoal mitochondrial function and its relation to motility. A chemical reaction (H2SO4, methylene blue solution, and zinc powder) was used to quantify methylene blue reduction. Absorbance measurements were made for 10 min at 609 nm in a narrow band spectrophotometer. In a second experiment, fresh ejaculates were assessed for concentration and motility evaluated with phase microscopy (37 degrees C). Semen was diluted to 100 million cells/mL in a sodium citrate-glucose buffer and methylene blue. Absorbance and motility were evaluated every 30 min for 2.5 h in a water-jacketed cuvette (41 degrees C). Methylene blue reduction rates and motility decreased at each subsequent period. Methylene blue reduction rates were correlated to sperm motility. Lastly, the methylene blue reduction rate was measured with a broad band spectrophotometer and compared with motility using similar conditions. Motility estimates were made on sperm from the cuvettes. Sperm motility was correlated to methylene blue reduction rates measured spectrophotometrically.

Animals↗

PubMed2004

[Mitochondrial function--role in insulin resistance and lipid metabolism].

Risk factors for the development of type 2 diabetes mellitus, including weight gain, lack of physical exercise and increasing age, are associated with an impaired mitochondrial function. Clinical studies could demonstrate a reduced mitochondrial activity in non-diabetic but insulin-resistant offsprings of type 2 diabetics. A key enzyme in the regulation of cellular energy supply and thus also in glucose and lipid metabolism is AMP-activated proteinkinase (AMPK). Pharmacological substances, which stimulate AMPK-activity ameliorate insulin resistance induced by free fatty acids. Various therapeutical interventions for the improvement of insulin sensitivity, including weight loss, physical exercise, as well as metformin and glitazones, increase AMPK activity.

AMP-Activated Protein Kinases↗

PubMed1998

Abnormal substrate levels that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients.

BACKGROUND: Impaired oxidative and energy metabolism are important features in Alzheimer's disease. These metabolic abnormalities may induce functional disturbances and are associated with significant cognitive impairment. OBJECTIVE: To determine whether mitochondrial function is altered by Alzheimer's disease, a quantitative analysis of substrates that enter the tricarboxylic acid cycle was carried out in cerebrospinal fluid (CSF) from Alzheimer patients. METHODS: Organic acid levels related to carbohydrate oxidation were measured in CSF from patients affected by dementia of Alzheimer type (n = 17) and from nondemented elderly controls (n = 17) using a gas chromatography/mass spectrometry system. CSF glucose and glutamine concentrations were determined by a quantitative enzymatic method and by ion exchange chromatography, respectively. RESULTS: Compared to age-matched controls, patients had a higher CSF level of lactate (p = 0.002) and a lower mean level of succinate (p = 0.002), fumarate (p = 0.003) and glutamine (p = 0.0005). The CSF glucose level was not modified. CONCLUSION: Our results suggest an impairment of mitochondrial oxidative metabolism in brain cells of patients with Alzheimer's disease.

Aged↗

PubMed2006

Real-time 2-photon imaging of mitochondrial function in perfused rat hearts subjected to ischemia/reperfusion.

BACKGROUND: Mitochondria play pivotal roles in cell death; the loss of mitochondrial membrane potential (delta psi(m)) is the earliest event that commits the cell to death. Here, we report novel real-time imaging of delta psi(m) in individual cardiomyocytes within perfused rat hearts using 2-photon laser-scanning microscopy, which has unique advantages over conventional confocal microscopy: greater tissue penetration and lower tissue toxicity. METHODS AND RESULTS: The Langendorff-perfused rat heart was loaded with a fluorescent indicator of delta psi(m), tetramethylrhodamine ethyl ester. Tetramethylrhodamine ethyl ester was excited with an 810-nm line of a Ti:sapphire laser, and its fluorescence in the heart cells was successfully visualized up to approximately 50 microm from the epicardial surface. Taking advantage of this system, we monitored the spatiotemporal changes of delta psi(m) in response to ischemia/reperfusion at the subcellular level. No-flow ischemia caused progressive delta psi(m) loss and a more prominent delta psi(m) loss on reperfusion. During ischemia/reperfusion, cells maintained a constant delta psi(m) for the cell-to-cell specific period of latency, followed by a rapid, complete, and irreversible delta psi(m) loss, and this process did not affect the neighboring cells. Within a cell, delta psi(m) loss was initiated in a particular area of mitochondria and rapidly propagated along the longitudinal axis. These spatiotemporal changes in delta psi(m) resulted in marked cellular and subcellular heterogeneity of mitochondrial function. Ischemic preconditioning reduced the number of cells undergoing delta psi(m) loss, whereas cyclosporin A partially inhibited delta psi(m) loss in each cell. CONCLUSIONS: Investigation of cellular responses in the natural environment will increase knowledge of ischemia/reperfusion injury and provide deeper insights into antiischemia/reperfusion therapy that targets mitochondria.

Animals↗

PubMed1988

T-2 toxin inhibits mitochondrial function in yeast.

T-2 toxin inhibits oxygen consumption of whole cells and purified mitochondria of Saccharomyces cerevisiae. Inhibition of mitochondrial respiration is not relieved by 2, 4-dinitrophenol, indicating that T-2 toxin inhibits mitochondrial function at the level of the electron transport chain. T-2 toxin inhibition of state 3 respiration (with succinate) is overcome by N, N, N', N'-tetramethyl-p-phenylenediamine, indicating inhibition of site II of the electron transport chain. T-2 toxin inhibits mitochondrial succinate dehydrogenase activity and increases mitochondrial NADH dehydrogenase activity.

2,4-Dinitrophenol↗

PubMed1994

Abnormal platelet mitochondrial function in patients affected by migraine with and without aura.

To investigate energy metabolism in migraine, we determined platelet mitochondrial enzyme activities in 40 patients with migraine with aura and in 40 patients with migraine without aura during attack-free intervals and in 24 healthy control subjects. NADH-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities in both patient groups were significantly lower than in controls (p < 0.01), while NADH-cytochrome-c-reductase activity was reduced only in migraine with aura (p < 0.01). No alteration in succinate-dehydrogenase was observed. Monoamine-oxidase activity differed between sexes (p < 0.05) but within each sex group no difference was observed between patients and controls. We hypothesize that the defect in mitochondrial enzymes observed indicates a systemic impairment of mitochondrial function in migraine patients.

Adolescent↗

PubMed2004

Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells.

The hepatitis B virus-X protein (HBx) regulates fundamental aspects of mitochondrial physiology. We show that HBx down-regulates mitochondrial enzymes involved in electron transport in oxidative phosphorylation (complexes I, III, IV, and V) and sensitizes the mitochondrial membrane potential in a hepatoma cell line. HBx also increases the level of mitochondrial reactive oxygen species and lipid peroxide production. HBx does not activate apoptotic signaling, although it sensitizes hepatoma cells to apoptotic signaling, which is dependent on reactive oxygen species. Increased intrahepatic lipid peroxidation in HBx transgenic mice demonstrated that oxidative injury occurs as a direct result of HBx expression. Therefore, we conclude that mitochondrial dysfunction is a crucial pathophysiological factor in HBx-expressing hepatoma cells and provides an experimental rationale in the investigation of mitochondrial function in rapidly renewed tissues, as in hepatocellular carcinomas.

Animals↗

PubMedDate not supplied

Alterations in hepatic mitochondrial function during total parenteral nutrition in immature rats.

To evaluate the effects of total parenteral nutrition (TPN) on hepatic mitochondrial function in immature rats, changes in hepatic energy charge levels and oxidative phosphorylation rates of hepatic mitochondria were studied along with the examination of serum chemical test. Male Wistar rats weighing 30 to 45 g were used and randomized into TPN (n = 8), enteral (n = 7), and control groups (n = 8). Parenteral and enteral groups were fed with TPN solution containing 19.3% dextrose, 3.19% amino acids, 1.05% fat emulsion, minerals and vitamins, and the control group with rat chow. The number of calories per kilogram per day was 550 x 1/4 on the 1st day, 550 x 1/2 on the 2nd, 550 x 3/4 on the 3rd, and 550 x 1 on the 4th day, based on the body weight on the 1st day. After the 5th day, 550 Kcal/kg/day was given, based on the body weight of the respective day. After 13-day feeding, hepatic energy charge (EC), phosphorylation rate (PR) of hepatic mitochondria and serum chemical examination were carried out. EC was 0.871 +/- 0.016 in the control group, 0.830 +/- 0.019 in the enteral, and 0.785 +/- 0.011 in TPN group (p less than 0.001, compared with control group). PR was 138.9 +/- 1.9, 133.0 +/- 6.7, 111.0 +/- 4.3, respectively, (p less than 0.05, compared with control and enteral groups). There was no difference between the three groups on SGOT, SGPT, and total bilirubin. TPN group showed a deterioration of hepatic phosphorylation rate and energy charge in spite of normal serum transaminase levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗

PubMed1984

The effects of beta-blocking agents on mitochondrial function in ischemic myocardium.

We investigated the protective effects of beta-adrenergic blocking agents on ischemia-induced mitochondrial dysfunction in 42 anesthetized mongrel dogs. The animals, divided into 6 groups of 7 dogs each, were premedicated with either saline for the controls, or D, L-propranolol (0.5 mg/kg), D-propranolol (0.5 mg/kg), D, L-acebutolol (2.5 mg/kg), D, L-pindolol (0.1 mg/kg), or L-isoproterenol (0.2 microgram/kg/min, for 10 min). Myocardial mitochondria were prepared from both the normal and the ischemic areas after 30 min of coronary ligation. The concentration of long-chain acyl-CoA was measured enzymatically. Respiratory control index, ADP/O, and the rate of oxygen consumption in State III of mitochondria were also measured. In the control group, acyl-CoA in ischemic mitochondria increased significantly compared with that in normal mitochondria, and mitochondrial dysfunction was observed. Administration of L-isoproterenol further increased acyl-CoA level and accelerated the dysfunction, whereas premedication with beta-blocking agents reduced the elevation of acyl-CoA level and prevented the dysfunction. Premedication with D-propranolol had no effect on mitochondria. Since the accumulation of acyl-CoA interferes with normal mitochondrial function, these results suggest that the protective effects of beta-blocking agents are based, at least in part, on the prevention of the accumulation of acyl-CoA esters.

Acebutolol↗

PubMed2004

Mitochondrial function in turkey skeletal muscle--impact on meat quality.

1. M. iliotibialis (MIT) and M. pectoralis (MP) of the BUT Big 6 and Kelly BBB turkey were characterised with respect to physical properties, mitochondrial function, metabolic state, morphology and meat quality. 2. Mitochondrial enzyme activity and respiration rates in MP declined with increasing age while glycolytic enzyme activity remained nearly constant. 3. There were no major differences between BUT Big 6 and Kelly BBB with respect to histological, histochemical or biochemical variables. In spite of the greater adult weight of BUT Big 6, body proportion was equal in both strains. 4. In agreement with the histochemical findings MIT showed higher oxidative capacities, while glycolytic enzyme activity was higher in MP. 5. Pyruvate was the best substrate for oxidative phosphorylation in MIT, but not in MP. Pyruvate dehydrogenase (PDH) activity was up to 15 times less in MP and blood lactate was correlated with intramuscular pH. 6. Turkey breast muscle was restricted in its ability to oxidise pyruvate, especially in those animals that tended to develop intramuscular acidosis post mortem. 7. It is concluded that the in vivo metabolic environment results in acidosis and impaired meat quality, at least in turkey M. pectoralis.

Acidosis↗

PubMed2004

Calcium oxalate monohydrate, a metabolite of ethylene glycol, is toxic for rat renal mitochondrial function.

Ethylene glycol poisoning can produce acute renal failure, requiring long-term hemodialysis to restore function. The mechanism of the renal failure is unknown, but is associated with tubular cell necrosis and ethylene glycol metabolism. The end metabolite of ethylene glycol is oxalic acid, the precipitation of which as calcium oxalate monohydrate (COM) crystals in the tubular lumen has been linked with the renal toxicity. Our recent studies suggest that COM is an intracellular toxicant to normal human proximal tubule cells in culture. The present studies were designed to assess whether COM or ionic oxalate alters mitochondrial function so as to lead to renal cell death. In isolated rat kidney mitochondria, COM produced a dose-dependent decrease in State 3 respiration (40% decrease at 0.05 mM COM with either succinate or glutamate/malate as substrate), without affecting either State 4 respiration or the ADP/O ratio. COM, from 0.01-0.05 mM also dose-dependently increased mitochondrial swelling, which was completely blocked by cyclosporin A. The inhibition of State 3 respiration, however, was not reversed by cyclosporin A administration. Potassium oxalate, at concentrations up to 5 mM did not inhibit mitochondrial respiration or induce swelling. These results suggest that COM, and not the oxalate ion, damages rat kidney mitochondria and induces the mitochondrial permeability transition, which may then lead to renal cell death. Since COM is transported intracellularly by kidney cells, the renal toxicity of ethylene glycol may result from inhibition of mitochondrial respiratory function in proximal tubular cells by COM crystals.

Animals↗

PubMed1989

Effects of Cassia obtusifolia (sicklepod) extracts and anthraquinones on muscle mitochondrial function.

Naturally occurring quinones and quinone-containing extracts of seeds of the toxic plant Cassia obtusifolia (sicklepod) affected muscle mitochondrial function. Aqueous suspensions and organic extracts of C. obtusifolia seeds slightly elevated plasma creatine kinase levels of Sprague-Dawley rats. These extracts were analyzed by fused silica capillary gas chromatography and found to contain nine anthraquinones and three anthrones. Urinary metabolites primarily consisted of beta-glucuronide conjugates of the anthraquinones. The three anthrones or conjugate analogues were not present in the urine in detectable amounts. Emodin, doxorubicin and organic extracts of C. obtusifolia inhibited NADH:cytochrome c oxidoreductase activity of bovine heart mitochondrial particles and NADH:CoQ oxidoreductase activity of porcine heart mitochondrial NADH dehydrogenase, whereas juglone was stimulatory. Relative quinone metabolism correlated with semiquinone formation rate and with redox potential. A protective effect of coenzyme Q against enzyme inhibition by anthraquinones was also observed.

Animals↗

PubMed1999

Fat balance and hepatic mitochondrial function in response to fat feeding in mature rats.

OBJECTIVE: To study the effects of fat feeding on fat balance and hepatic mitochondrial function in postpubertal male rats. DESIGN: Rats were fed low fat, medium fat or high fat diet for 15 days. MEASUREMENTS: Energy balance, body composition, resting metabolic rate (RMR), mitochondrial state 3 and state 4 oxygen consumption rates, succinic dehydrogenase (EC 1.3.99.1) and mitochondrial alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) activities. RESULTS: Rats fed medium fat or high fat diet, in comparison with rats fed low fat diet, showed a significantly greater metabolisable energy intake and energy expenditure. In addition, body energy and lipid gains were significantly higher in rats fed medium fat or high fat diet than in rats fed low fat diet. Mitochondrial respiration and enzymatic activities were not affected by fat feeding. CONCLUSION: These results indicate that in postpubertal rats fed high fat diets, the increase in energy expenditure counteracts only in part the excess fat deposition. This is probably due to the impairment in regulatory responses, and enhances thermogenesis.

Adipose Tissue↗