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Results for “Mitochondrial function”

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PubMed1997

Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury.

Glutamate-induced excitotoxicity involving the formation of reactive oxygen species (ROS) has been implicated in neuronal dysfunction and cell loss following ischemic and traumatic injury to the central nervous system (CNS). ROS are formed in mitochondria when energy metabolism is compromised, and are inactivated by the ROS scavengers superoxide dismutase (SOD), catalase, and glutathione (GSH). ROS can impair the function of several cellular components including proteins, nucleic acids, and lipids. In the present study, we measured indicators of mitochondrial metabolic activity, ROS formation, lipid peroxidation, and antioxidant enzyme activities in synaptosomes obtained from rat spinal cord at early times following traumatic injury. Mitochondrial metabolic activity was found to significantly decrease as early as 1 h following injury, and continued to be compromised over the remaining postinjury time points. ROS formation was found to be significantly increased at 4 and 24 h following injury, while lipid peroxidation levels were found to be significantly increased in the injured spinal cord at 1 and 24 h, but not 4 h following injury. SOD enzyme activity was unchanged at all postinjury time points, while catalase activity and GSH levels were significantly increased at 24 h following injury. These findings indicate that impaired mitochondrial function, ROS, and lipid peroxidation occur soon after traumatic spinal cord injury, while the compensatory activation of molecules important for neutralizing ROS occurs at later time points. Therapeutic strategies aimed at facilitating the actions of antioxidant enzymes or inhibiting ROS formation and lipid peroxidation in the CNS may prove beneficial in treating traumatic spinal cord injury, provided such treatments are initiated at early stages following injury.

Animals↗

PubMedDate not supplied

Evaluation of rhodamine 123 as a probe for monitoring mitochondrial function in Trypanosoma brucei spp.

Rhodamine 123, a membrane potential-specific dye, has been evaluated as a probe to monitor the function of the mitochondrion in long slender bloodstream and procyclic trypomastigotes of several Trypanosoma brucei spp. By epifluorescence microscopy, mitochondrial development has been followed in long slender bloodstream and procyclic organisms stained with rhodamine 123. To photograph stained long slender bloodstream forms, it was necessary to develop a method to completely immobilize viable organisms. In both parasite forms, as the cell cycle progressed, the mitochondrion developed from a thread-like structure to a highly branched organelle. A dramatic reorganization occurred preceding cytokinesis to produce two progeny thread-like structures which were partitioned into newly formed daughter cells. The organelle within the long slender trypomastigote was found to stain optimally at 0.3 microgram/ml of rhodamine 123, while the procyclic form required 3.0 micrograms/ml. The results suggest that the plasma membrane potential is higher in the long slender parasite than in the procyclic form. The effects of inhibitors that disrupt mitochondrial function were examined in long slender and procyclic parasites, and some of these agents were shown to affect rhodamine 123 accumulation and retention. In long slender trypomastigotes the trypanosome alternative oxidase does not appear to be coupled to proton pumping, whereas in procyclic organisms the effects of inhibitors indicate that this oxidase may be coupled to a pathway that is branched preceding an antimycin A1-sensitive site.

Animals↗

PubMed1975

Embryonic development and mitochondrial function. 1. Effects of chloramphenicol infusion on the synthesis of cytochrome oxidase and DNA in rat embryos during late organogenesis.

Cytochrome oxidase, which is partially synthesized by the mitochondrion, was used as a measure for the development of mitochondrial function in rat embryos during the late stage of organogenesis. For this purpose the specific inhibitor of mitochondrial protein synthesis, chloramphenicol (CAP), served as a tool. Due to the rapid elimination rate of CAP from rats, a method for continuous infusion which would not cause immobilization to the animals was devised. 1. Pharmacokinetic studies proved that CAP reaches the embryo before placentation. Concentrations of CAP in the embryo are as high as they are in the maternal serum (about 20 mug/ml serum or g embryo) and thuse are sufficiently in supply for the inhibition of mitochondrial proteins synthesis, if 1000 mg/kg CAP are infused intravenously per 24 hrs. CAP is partially excluded from the embryonic compartment after the placental barrier has fully developed: whereas CAP concentration in the maternal serum remains at about 20 mug/ml, the concentration in the embryonic compartment drops to about 10 mug/g embryonic tissue during day 13 of gestation. 2. The average cytochrome oxidase activity per cell is very low (about 1 nmole O2/min X mug DNA-1) in embryonic tissue as it is in many other rapidly proliferating tissues. It is 15-60 times higher in slowly proliferating tissues, as, for example, the adult rat liver or brain (greater than 14 nmoles O2/min X mug DNA-1). 3. When the infusion technique is applied on day 12 of gestation, a sufficiently high concentration of CAP in embryonic tissue can be obtained to inhibit the synthesis of cytochrome oxidase. In constrast to tissues of an adult organism-as in the case of liver after partial hepatectomy- in embryonic tissues this limitation in the availablity of cytochrome oxidase appearently results in a critical reduction of energy production, which subsequently affects the DNA synthesis and embryonic growth. 4. The possible relevance and applicability of these experimental findings to man is discussed.

Animals↗

PubMed2001

Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.

Heart mitochondria from heterozygous (Sod2(-/+)) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased mitochondrial oxidative damage as demonstrated by a decrease in the activities of iron sulfhydryl proteins sensitive to oxygen stress (aconitase and reduced nicotinamide adenine dinucleotide-oxidoreductase). Mitochondrial function was altered in the Sod2(-/+) mice, as shown by decreased respiration by complex I and an increase in the sensitivity of the permeability transition to induction by calcium and t-butylhydroperoxide. The increased induction of the permeability transition in heart mitochondria from Sod2(-/+.)mice was associated with increased release of cytochrome c and an increase in DNA fragmentation. Cardiomyocytes isolated from neonatal Sod2(-/+) and Sod2(-/-) mice were more sensitive to cell death than cardiomyocytes from Sod2(+/+) mice after t-butylhydroperoxide treatment, and this increased sensitivity was prevented by inhibiting the permeability transition with cyclosporin A. These experiments demonstrate that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.

Aconitate Hydratase↗

PubMed1990

Analysis of sperm cell viability, acrosomal integrity, and mitochondrial function using flow cytometry.

A triple staining procedure was developed to evaluate bull spermatozoa using flow cytometry. Flow cytometric estimates of cell viability, measured by propidium iodide (PI) exclusion, and acrosomal integrity, measured by Pisum sativum agglutinin (PSA) binding acrosomal contents, were equivalent to estimates made by using standard laboratory assays. Mitochondrial function, measured by rhodamine 123 (R123) fluorescence, was depressed by the mitochondrial inhibitors rotenone (64%) or monensin (52%), establishing that mitochondrial damage can be detected. Dilauroylphosphatidylcholine (PC12) or lysophosphatidylcholine (LPC) was used to destabilize sperm membranes. When challenged with 15-30 microM PC12, selective exposure of PSA binding sites occurred without induction of PI uptake or loss of R123 staining. However, PC12 concentrations greater than 60 microM resulted in a loss of R123 fluorescence intensity. In contrast, greater than 1200 microM LPC was required to expose PSA binding sites, which also resulted in PI uptake. By using flow cytometry, these three stains in combination can be used to correlate three different features simultaneously on individual spermatozoa and assay thousands of cells per sample without extensive preparation.

Acrosome↗

PubMed2006

Expression of transforming K-Ras oncogene affects mitochondrial function and morphology in mouse fibroblasts.

K-ras transformed fibroblasts have been shown to have a stronger dependence from glycolysis, reduced oxidative phosphorylation ability and a fragility towards glucose depletion compared to their immortalized, normal counterparts. In this paper, using RNA profiling assays and metabolic perturbations, we report changes in expression of genes encoding mitochondrial proteins and alterations in mitochondrial morphology that correlate with mitochondrial functionality. In fact, unlike normal cells, transformed cells show reduced ATP content and inability to modify mitochondria morphology upon glucose depletion. Being reverted by GEF-DN expression, such morphological and functional changes are directly connected to Ras activation. Taken together with reported partial mitochondrial uncoupling and more sustained apoptosis of transformed cells, our results indicate that activation of the Ras pathway strikingly impacts on energy and signaling-related aspects of mitochondria functionality, that in turn may affect the terminal phenotype of transformed cells.

Adenosine Triphosphate↗

PubMed1993

Role of lipid peroxidation in impairment of mitochondrial function at complex I by methyl isocyanate treatment of rats in vivo.

The subcutaneous administration of methyl isocyanate (MIC) in 1.0 LD50 dose in rats caused a significant effect on hepatic mitochondrial function only at complex I region of the respiratory chain. MIC administration at 1.0 LD50 dose also resulted in significant increases in malondialdehyde and ferrous ion concentration in liver mitochondria. It is suggested that the augmented lipid peroxidation in hepatic mitochondria, catalyzed by iron, possibly mobilized from intracellular stores leads to the inhibition of enzymes of mitochondrial respiration at complex I region, in vivo, in rats receiving a lethal dose of MIC subcutaneously.

Animals↗

PubMed1996

Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio.

1. Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. 2. This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio. 3. Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels > 6.0 mmol l-1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects. 4. Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P < 0.05 and P < 0.001). The difference was not significant between fibratetreated patients and untreated patients. 5. Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l-1 +/- 0.04) than in untreated hypercholesterolaemic patients (0.95 mg l-1 +/- 0.09; P < 0.05). 6. We conclude that statin therapy can be associated with high blood lactate/ pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.

Adult↗

PubMed2000

Mitochondrial function in flying honeybees (Apis mellifera): respiratory chain enzymes and electron flow from complex III to oxygen.

The biochemical bases for the high mass-specific metabolic rates of flying insects remain poorly understood. To gain insights into mitochondrial function during flight, metabolic rates of individual flying honeybees were measured using respirometry, and their thoracic muscles were fixed for electron microscopy. Mitochondrial volume densities and cristae surface densities, combined with biochemical data concerning cytochrome content per unit mass, were used to estimate respiratory chain enzyme densities per unit cristae surface area. Despite the high content of respiratory enzymes per unit muscle mass, these are accommodated by abundant mitochondria and high cristae surface densities such that enzyme densities per unit cristae surface area are similar to those found in mammalian muscle and liver. These results support the idea that a unit area of mitochondrial inner membrane constitutes an invariant structural unit. Rates of O(2) consumption per unit cristae surface area are much higher than those estimated in mammals as a consequence of higher enzyme turnover rates (electron transfer rates per enzyme molecule) during flight. Cytochrome c oxidase, in particular, operates close to its maximum catalytic capacity (k(cat)). Thus, high flux rates are achieved via (i) high respiratory enzyme content per unit muscle mass and (ii) the operation of these enzymes at high fractional velocities.

Animals↗

PubMed2003

Bcl-XL maintains mitochondrial function in murine astrocytes deprived of glucose.

Bcl-XL is a protein that blocks both apoptotic and necrotic cell death. The authors have previously shown that it is effective in maintaining mitochondrial membrane potential during glucose deprivation in cultured astrocytes. To further investigate the mechanism involved, the authors studied mitochondrial function and cytochrome c release. Oxygen consumption was monitored to assess oxidative respiration. State III respiration decreased significantly as early as 3 h after removal of glucose. At this time mitochondria hyperpolarize but cytochrome c is not yet released. Damage to the electron transport chain is not responsible for this change because uncoupled respiration was unchanged at this time point. At 5 h of glucose deprivation, when mitochondrial depolarization was observed, state IV respiration increased significantly, cytochrome c began to be released, and mitochondrial morphology changed from elongated to punctate. When Bcl-XL was overexpressed normal state III respiration and mitochondrial morphology were maintained and cytochrome c release was inhibited in the face of glucose deprivation stress.

Animals↗

PubMed1994

Effect of acute ethanol exposure on cultured fetal rat hepatocytes: relation to mitochondrial function.

Studies from our laboratory have shown that short-term ethanol exposure inhibits epidermal growth factor-dependent replication of cultured fetal rat hepatocytes, along with a drop in ATP level, and that these effects could be caused, at least in part, by ethanol-induced oxidative stress. In these prior studies, mitochondrial morphology was abnormal and membrane lipid peroxidation products were increased, along with reduced transmembrane potential and enhanced permeability to sucrose. To define the effects of ethanol on mitochondrial function further, the present study examines the impact of ethanol exposure on mitochondrial electron transport chain components. A 24-hr exposure of cultured fetal rat hepatocytes to ethanol (2.5 mg/ml) reduced mitochondrial complex I activity by 16% (p < 0.05), complex IV by 28% (p < 0.05), and succinate dehydrogenase by 23% (p < 0.05). This reduction was paralleled by lower ADP translocase activity (24%, p < 0.05) and diminished mitochondrial glutathione (GSH) (20%, p < 0.05). Pretreatment with 0.1 mM S-adenosyl methionine, before ethanol exposure, normalized mitochondrial GSH along with activities of complex I, complex IV, and succinate dehydrogenase. A 3-hr exposure of isolated mitochondria (which do not metabolize ethanol) to ethanol (2.5 mg/ml), inhibited the activities of complex I (19%, p < 0.05), complex IV (24%, p < 0.05), and of ATP synthesis (20%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Activation of mitochondrial functions by malotilate in relation to accelerated liver regeneration in partially hepatectomized rats.

Malotilate was orally administered to rats at a dose of 100 mg/kg 2 hr after partial hepatectomy. Mitochondrial state 3 respiration of the liver increased significantly from 23.4 nmol/min/mg protein in the control rats to 29.3 nmol/min/mg protein in the rats administered with malotilate at 3 hr after the hepatectomy (1 hr after the administration). The administration also resulted in higher tendencies in the respiratory control ratio after 3, 6 or 20 hr (1, 4 or 18 hr after the administration) than in the control rats. Although partial hepatectomy made hepatic ATP concentration remarkably low, it gradually increased (from 1.53 mumol/g liver after 3 hr) to a level of 2.03 mumol/g liver after 20 hr in the rats administered with malotilate. No increase in ATP concentration was observed in the control rats. Correspondingly, the adenylate energy charge also showed higher tendencies in the malotilate administered rats. From these result, it is supposed that malotilate activates the mitochondrial functions which results in the increases of ATP concentration and adenylate energy charge. These changes in energy metabolism can be associated with accelerated regeneration of the liver by malotilate.

Adenosine Monophosphate↗

PubMed2003

Methodological characterization of the 2-keto [1-13C]isocaproate breath test to measure in vivo human mitochondrial function: application in alcoholic liver disease assessment.

BACKGROUND: The 2-keto[1-13C]isocaproate oxidation measurement has been shown as a helpful tool in the in vivo assessment of liver mitochondrial function. METHODS: The aim of this work was to study the variability of the 2-keto[1-13C]isocaproate breath test in 24 healthy controls (8 men and 16 women) and to evaluate its clinical usefulness in 20 patients (14 men and 6 women) with liver disease (7 men with history of alcoholism). Breath test was performed by measuring 13CO2 enrichment in breath before and after the oral administration of the tracer and by using isotope ratio mass spectrometry. RESULTS: The intrasubject and intersubject variability of the percentage of tracer oxidized were 8 and 14%, respectively. The 2-keto[1-13C]isocaproate oxidation in women was faster (p = 0.004) and tended to be higher (p = 0.050) than in men. The percentage of oxidized tracer was lower in those patients with alcoholic liver disease than in healthy volunteers (p = 0.001) and in nonalcoholic patients (p = 0.003). CONCLUSIONS: The percentage of tracer oxidized appears as a convenient parameter to detect impairment in liver mitochondrial oxidation related to alcoholism by the 2-keto[1-13C]isocaproate breath test, establishing different cutoff values depending on gender.

Adolescent↗

PubMed2005

Mitochondrial function is a critical determinant of IL-1-induced ERK activation.

Interleukin-1 (IL-1) is a potent, proinflammatory cytokine, but local environmental factors in inflamed sites or in sepsis may affect cell metabolism and energetics, including the amplitude and duration of IL-1-induced signals, thereby leading to loss of tissue homeostasis. Currently, the mechanisms by which disruption of cell energetics affects inflammatory signaling are incompletely understood. Here, we examined the impact of cell energetics and mitochondrial function on the regulation of IL-1-induced Ca2+ signals and ERK activation in human gingival fibroblasts, cells that are important targets for IL-1-induced destruction of extracellular matrix in inflamed connective tissues. In untreated cells, IL-1 induced a prolonged increase of free intracellular calcium, which was required for ERK activation. Inhibition of cellular energetics by selective depolarization of mitochondria blocked Ca2+ uptake and almost completely abolished IL-1-induced cytosolic Ca2+ signals and ERK activation. IL-1 caused rapid Ca2+ release from the endoplasmic reticulum (ER), concomitant with mitochondrial Ca2+ uptake from ER and non-ER stores. Disruption of mitochondrial energetics abrogated IL-1 induced Ca2+ release from the ER but left other vital cellular functions intact. The negative effect of mitochondrial depolarization on ER release was bypassed by BAPTA/AM, indicating that mitochondrial Ca2+ buffering is the key mechanism in regulating ER release. Thus, in gingival fibroblasts, mitochondrial Ca2+ uptake is essential not only for shaping the kinetics and duration, but also the generation of, IL-1-induced Ca2+ signals. Consequently, mitochondria regulate key downstream effectors of IL-1, including MAP kinases.

Adenosine Triphosphate↗

PubMed1999

Optical methods for probing mitochondrial function in brain slices.

Brain slice preparations have become useful tools for studying multiple facets of normal brain function and for investigations of brain pathophysiology. Recently, a variety of neurological disorders have been linked to dysfunction of brain mitochondria. In this report we discuss optical methods for probing mitochondrial function in brain slices. Absorption spectrophotometric and spectrofluorometric techniques are described for measuring changes in the redox activity of mitochondrial cytochromes and the primary respiratory chain substrate nicotinamide adenine dinucleotide (NADH), respectively. A spectrofluorometric method is described also for measuring changes in mitochondrial membrane potential using the potential-sensitive fluorescent indicator JC-1. These methods used together have proven to be useful for studying dysfunction of mitochondria following in vitro ischemia in hippocampal slices, and might also be valuable for investigations of mitochondrial involvement in other neurological disorders.

Animals↗

PubMed1998

Cisplatin induced intermediate filament reorganization and altered mitochondrial function in 3T3 cells and drug-sensitive and -resistant Walker 256 cells.

Cisplatin has acute but reversible effects on the organization of the intermediate filament component of the cytoskeleton as well as the mitochondrial function of cultured 3T3 cells. These effects do not involve major changes in total cell or cytoskeletal protein synthesis and appear to be distinct from the long-term cytotoxicity produced by the drug. Cells treated with similar concentrations of second-generation platinum compounds, which have reduced nephrotoxic effects in vivo, do not exhibit alterations in intermediate filament organization nor mitochondrial rhodamine 123 fluorescence. Similar studies with cisplatin-sensitive and -resistant lines of rat Walker 256 cells indicated that the drug-induced intermediate filament collapse and decreased mitochondrial rhodamine 123 fluorescence correlated with the susceptibility of these cells to the lethal effects of cisplatin.

3T3 Cells↗

PubMed1989

Evaluation of mitochondrial function by measuring the heat production in state 3 and state 4 respiration.

Using a microcalorimetric method, we have measured the heat production in states 3 and 4 respiration of a mitochondrial preparation from rat heart ventricle. Adenosine triphosphate production in state 3 respiration was also determined for the same preparation after heat production was measured. In Tris-buffered solution with pyruvate and malate used as substrates, the total heat production in states 3 and 4 respiration for a 10-min reaction period were about 709 and 207 mJ/mg of mitochondrial protein, respectively. 2,4-Dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation, increased the heat production in both states 3 and 4 respiration. On the other hand, antimycin A1, an inhibitor of the electron transport system, decreased the heat production in both states. When ventricle mitochondrial dysfunction was induced by the in vivo administration of a high dose of isoproterenol, heat production was increased in state 4 respiration. These results indicate that the calorimetric method can be used to evaluate the mitochondrial function.

Animals↗

PubMed2005

SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes.

SIRT3 is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene, which mediates the effect of caloric restriction on life span extension in yeast and Caenorhabditis elegans. Because adipose tissue is essential in energy homeostasis and also plays a role in life span determination, we decided to investigate the function of sirtuin members in fat. We report here that murine SIRT3 is expressed in brown adipose tissue and is localized on the mitochondria inner membrane. Caloric restriction activates SIRT3 expression in both white and brown adipose. Additionally, cold exposure up-regulates SIRT3 expression in brown fat, whereas elevated climate temperature reduces the expression. Enforced expression of SIRT3 in the HIB1B brown adipocytes enhances the expression of the uncoupling protein PGC-1alpha, UCP1, and a series of mitochondria-related genes. Both ADP-ribosyltransferase and deacetylase activities of SIRT3 are required for this action. Furthermore, the SIRT3 deacetylase mutant exhibits a dominant negative effect by inhibiting UCP1 expression. This inhibitive effect can be abolished by the coexpression of PGC-1alpha, indicating a major role of PGC-1alpha in the SIRT3 action. In addition, SIRT3 stimulates CREB phosphorylation, which reportedly activates PGC-1alpha promoter directly. Functionally, sustained expression of SIRT3 decreases membrane potential and reactive oxygen species production while increasing cellular respiration. Finally, SIRT3, along with genes related to mitochondrial function, is down-regulated in the brown adipose tissue of several genetically obese mice. In summary, our results demonstrate that SIRT3 activates mitochondria functions and plays an important role in adaptive thermogenesis in brown adipose.

ADP Ribose Transferases↗