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PubMed2005

Inhibition of MG132-induced mitochondrial dysfunction and cell death in PC12 cells by 3-morpholinosydnonimine.

The effect of 3-morpholinosydnonimine (SIN-1) against the cytotoxicity of MG132, a proteasome inhibitor, in differentiated PC12 cells was assessed by measuring the effect on the mitochondrial membrane permeability. Treatment of PC12 cells with MG132 resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS), and depletion of GSH. Addition of SIN-1, a producer of nitric oxide (NO) and superoxide, differentially reduced the MG132-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 150 microM. Carboxy-PTIO, superoxide dismutase, Mn-TBAP, and ascorbate prevented the inhibitory effect of SIN-1 on the cytotoxicity of MG132. SIN-1 inhibited the MG132-induced change in the mitochondrial membrane permeability, ROS formation and decrease in GSH contents in PC12 cells. S-nitroso-N-acetyl-DL-penicillamine reduced the MG132-induced cell death in PC12 cells, whereas peroxynitrite and H2O2 did not affect the cytotoxicity of MG132. The results suggest that NO and superoxide liberated from SIN-1 exert an inhibitory effect against the cytotoxicity of MG132. SIN-1 may inhibit the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability that is associated with oxidative damage.

Animals↗
PubMed2005

Role of nitric oxide-induced mtDNA damage in mitochondrial dysfunction and apoptosis.

An increasing body of evidence suggests that nitric oxide (NO) can be cytotoxic and induce apoptosis. NO can also be genotoxic and cause DNA damage and mutations. It has been shown that NO damages mitochondrial DNA (mtDNA) to a greater extent than nuclear DNA. Previously, we reported that conditional targeting of the DNA repair protein hOGG1 into mitochondria using a mitochondria targeting sequence (MTS) augmented mtDNA repair of oxidative damage and enhanced cellular survival. To determine whether enhanced repair resulting from augmented expression of hOGG1 could also protect against the deleterious effects of NO, we used HeLa TetOff/MTS-OGG1-transfected cells to conditionally express hOGG1 in mitochondria. The effects of additional hOGG1 expression on repair of NO-induced mtDNA damage and cell survival were evaluated. These cells, along with vector transfectants, in either the presence or absence of doxycycline (Dox), were exposed to NO produced by the rapid decomposition of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (PAPA NONOate). Functional studies revealed that cells expressing recombinant hOGG1 were more proficient at repairing NO-induced mtDNA damage, which led to increased cellular survival following NO exposure. Moreover, the results described here show that conditional expression of hOGG1 in mitochondria decreases NO-induced inhibition of ATP production and protects cells from NO-induced apoptosis.

Apoptosis↗
PubMed2005

4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one induces mitochondrial dysfunction and apoptosis upon its intracellular oxidation.

We investigated the mechanism of cell death induced by a furoquinolinone derivative, namely, 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), in the dark. Mitochondrial depolarization was found to be a causative event in HOFQ-induced apoptosis that was blunted either by replacing the 4-hydroxymethyl group with a methyl one, or by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase (ADH). In vitro enzymatic assay demonstrated that HOFQ is a substrate of ADH. In isolated mitochondria HOFQ was without effect, whereas in the presence of ADH and NAD(+) it caused the opening of the permeability transition pore, indicating that HOFQ-oxidized products affect mitochondrial function directly. Finally, an analogue bearing the formyl group at the C-4 position mimicked all the effects exerted by HOFQ. In conclusion, these results suggest that the direct action on mitochondria of HOFQ-oxidized products are responsible for their cytotoxicity, which might be exacerbated, but hardly determined, by photodynamic action and/or binding to DNA.

Alcohol Dehydrogenase↗
PubMed2005

Inhibition of 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells by sulfonylurea glibenclamide.

The present study investigates the effect of sulfonylurea glibenclamide on the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+) in differentiated PC12 cells in relation to changes in the mitochondrial membrane permeability. Glibenclamide and tolbutamide reduced the MPP+-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 5-10 microM. Despite the toxic effect at 20 microM, sulfonylureas showed an inhibitory effect. N-Acetylcysteine, superoxide dismutase, catalase, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and Mn(III) tetrakis(4-benzoic acid)porphyrin chloride inhibited the cytotoxicity of MPP+. Glibenclamide attenuated the nuclear damage, changes in the mitochondrial membrane permeability, caspase-3 activation and formation of reactive oxygen species due to MPP+ in PC12 cells. The results show that glibenclamide may reduce the MPP+-induced viability loss in PC12 cells by suppressing the changes in the mitochondrial membrane permeability, leading to the release of cytochrome c and subsequent activation of caspase-3, which are associated with the increased reactive oxygen species formation and depletion of GSH.

1-Methyl-4-phenylpyridinium↗
PubMed1983

Mitochondrial dysfunction induced by pancreatitis-associated ascitic fluid.

Acute hemorrhagic pancreatitis (AHP) involves multiple organ failure probably caused by the toxic factor(s) released in pancreatitis-associated ascitic fluid (PAAF). We found that PAAF interferes with hepatic mitochondrial respiration resulting in severe disturbances in respiratory control (RCR) and ADP/O ratios. Pancreatitis was induced in dogs by retrograde pancreatic duct infusion and the resultant PAAF was centrifuged, filtered, and frozen until used. Two human PAAFs collected from AHP patients were treated in a similar manner. Rat liver mitochondrial oxygen uptake was measured at 30 degrees C before and after addition of ADP and PAAF. Paired control runs were made using pooled heat-inactivated dog serum. Tests with nine canine PAAFs showed a mean increase of 120% in state 4 respiration (P less than 0.0001). After exposure to PAAF, addition of ADP to previously coupled mitochondria did not induce state 3 respiration. The human PAAFs both showed significant increases in state 4 respiration (P less than 0.01) and a marked decrease in RCR. Dose-response tests with human and canine PAAFs showed a positive correlation between percentage increase in state 4 respiration and the concentration of PAAF used. These results confirm the presence in PAAF of mitotoxic substance(s) which cause irreversible mitochondrial damage. Inhibition of coupled mitochondrial respiration by PAAF with the resultant fall in ATP may be the causative agent for the tissue and organ damage observed in AHP.

Animals↗
PubMed2005

Burn injury causes mitochondrial dysfunction in skeletal muscle.

Severe burn trauma is generally followed by a catabolic response that leads to muscle wasting and weakness affecting skeletal musculature. Here, we perform whole-genome expression and in vivo NMR spectroscopy studies to define respectively the full set of burn-induced changes in skeletal muscle gene expression and the role of mitochondria in the altered energy expenditure exhibited by burn patients. Our results show 1,136 genes differentially expressed in a mouse hind limb burn model and identify expression pattern changes of genes involved in muscle development, protein degradation and biosynthesis, inflammation, and mitochondrial energy and metabolism. To assess further the role of mitochondria in burn injury, we performed in vivo (31)P NMR spectroscopy on hind limb skeletal muscle, to noninvasively measure high-energy phosphates and the effect of magnetization transfer on inorganic phosphate (P(i)) and phosphocreatine (PCr) resonances during saturation of gammaATP resonance, mediated by the ATP synthesis reactions. Although local burn injury does not alter high-energy phosphates or pH, apart from PCr reduction, it does significantly reduce the rate of ATP synthesis, to further implicate a role for mitochondria in burn trauma. These results, in conjunction with our genomic results showing down-regulation of mitochondrial oxidative phosphorylation and related functions, strongly suggest alterations in mitochondrial-directed energy expenditure reactions, advancing our understanding of skeletal muscle dysfunction suffered by burn injury patients.

Adenosine Triphosphate↗
PubMed2001

Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation.

BACKGROUND/AIMS: Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A. METHODS: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice. RESULTS: Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 microM) concentrated in mitochondria, collapsed the membrane potential, inhibited beta-oxidation, and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 microM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell adenosine triphosphate (ATP) and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body weight), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor. CONCLUSIONS: Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concentrations or doses of buprenorphine is mainly related to its mitochondrial effects.

Adenosine Triphosphate↗
PubMed2000

AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction.

Rapid Zn2+ influx through Ca2+-permeable AMPA/kainate (Ca-A/K) channels triggers reactive oxygen species (ROS) generation and is potently neurotoxic. The first aim of this study was to determine whether these effects might result from direct mitochondrial Zn2+ uptake. Adapting the mitochondrially sequestered divalent cation sensitive probe, rhod-2, to visualize mitochondrial Zn2+, present studies indicate that Zn2+ is taken up into these organelles. The specificity of the signal for Zn2+ was indicated by its reversal by Zn2+ chelation, and its mitochondrial origin indicated by its speckled extranuclear appearance and by its elimination upon pretreatment with the mitochondrial protonophore, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP). Consistent with inhibition of mitochondrial Zn2+ uptake, FCCP also slowed the recovery of cytosolic Zn2+ elevations in Ca-A/K(+) neurons. Further studies sought clues to the high toxic potency of intracellular Zn2+. In experiments using the mitochondrial membrane polarization (DeltaPsi(m))-sensitive probe tetramethylrhodamine ethyl ester and the ROS-sensitive probe hydroethidine, brief kainate exposures in the presence of 300 microM Zn2+ (with or without Ca2+) resulted in prolonged loss of DeltaPsi(m) and corresponding prolonged ROS generation in Ca-A/K(+) neurons, in comparison to the more rapid recovery from loss of DeltaPsi(m) and transient ROS generation after kainate/1.8 mM Ca2+ exposures.

Animals↗
PubMedDate not supplied

Glucose deprivation induces mitochondrial dysfunction and oxidative stress in PC12 cell line.

Glucose metabolism plays a pivotal role in many physiological and pathological conditions. To investigate the effect of hypoglycemia (obtained by glucose deprivation) on PC12 cell line, we analyzed the cell viability, mitochondrial function (assessed by MTT reduction, cellular ATP level, mitochondrial transmembrane potential), and the level of reactive oxygen species (ROS) after glucose deprivation (GD). Upon exposure to GD, ROS level increased and MTT reduction decreased immediately, intracellular ATP level increased in the first 3 hours, followed by progressive decrease till the end of GD treatment, and the mitochondrial transmembrane potential (deltapsi(m)) dropped after 6 hours. Both necrosis and apoptosis occurred apparently after 24 hours which was determined by nuclei staining with propidium iodide(PI) and Hoechst 33342. These data suggested that cytotoxicity of GD is mainly due to ROS accumulation and ATP depletion in PC12 cells.

Adenosine Triphosphate↗
PubMed2005

Mitochondrion-targeted photosensitizer enhances the photodynamic effect-induced mitochondrial dysfunction and apoptosis.

Recently, the mitochondrion has been considered as a novel pharmacological target for anticancer therapy due to its crucial role involved in arbitrating cell apoptosis. We have previously demonstrated that 488-nm laser irradiation induced a specific mitochondrial reactive oxygen species (mROS) formation and apoptotic death. In this study, we used a second generation of photosensitizers, the benzoporphyrin-derivative monoacid ring A (BPD-MA). We investigated specifically mechanisms at the mitochondrial level for BPD-MA coupled with 690-nm laser irradiation, the photodynamic effect (PDE) of BPD-MA, using conventional and laser scanning imaging microscopy in intact C6 glioma cells. We demonstrated BPD-MA localized mainly in the mitochondrial area. The phototoxicity induced by 1-10 J 690-nm laser irradiation was minor as compared to that induced by 488-nm laser irradiation. Unlike other mitochondrion-targeted photosensitizers, the dark toxicity induced by BPD-MA (0.05-5 mg/mL, effective doses used for the PDE) was relatively low. Nevertheless, the PDE of BPD-MA using 0.5 mg/mL coupled with 5J 690-nm irradiation induced profound and rapid (< 1 min) mitochondrial swelling, mROS formation, and severe plasma membrane blebbing as compared to that induced by 488-nm laser irradiation (< 10 min). Later, the PDE of BPD-MA resulted in positive propidium iodide cell-death stain and positive TUNEL apoptotic nuclear stain and DNA laddering. Finally, the PDT of BPD-MA also instantaneously promoted the mitochondrion to diminish its covalent binding with a mitochondrial marker, MitoTracker Green. We conclude that the PDT of BPD-MA targeted primarily and compellingly the mitochondrion to induce effective mitochondria-mediated apoptosis and thus may serve as a powerful photosensitizer for clinical cancer therapy.

Animals↗
PubMedDate not supplied

Energetic depression caused by mitochondrial dysfunction.

Mitochondria not only provide most of the ATP needed for cell work and numerous specific anabolic and catabolic functions, they also contribute to Ca++ signalling and play a key role in the pathway to cell death. Impairment of mitochondrial functions caused by mutations of the mt-genome or by acute processes, is responsible for numerous diseases. Decreased concentrations of adenine nucleotides, leaky outer and inner mitochondrial membranes, and decreased activities of respiratory chain enzymes contribute to depression of cellular energy metabolism, one of the most important consequences of mitochondrial impairment as characterized by decreased cytosolic phosphorylation potentials.

Adenine Nucleotides↗
PubMed1996

[Mitochondrial dysfunction in acute lung injury caused by endothelial-1 and leukotoxin].

We studied whether endothelin-1 (ET-1) and leukotoxin (Lx), which have a different effects on vascular tone in isolated perfused rat lungs, also have different effects on mitochondrial function in edematous lung injury. Lung mitochondria were extracted from isolated perfused rat lungs exposed to each mediator. In lungs exposed to 0.5 nmol of ET-1, lung wet weight increased with a markedly elevated perfusion pressure but with no increase in the release of lactate dehydrogenase (LDH), an index of cell damage, into the perfusate. Neither mitochondrial respiration rate no ATP content in the lung tissue differed from those of untreated lungs. In contrast, in lungs treated with 30 mumol of Lx, lung wet weight markedly increased despite a small elevation of perfusion pressure; release of LDH into the perfusate increased, and the mitochondrial respiration rate in state 3 adn 4 significantly decreased while the ATP content in the lung tissue was less than in untreated lungs. We also examined cellular and mitochondrial damage in hydrostatic lung edema caused by raising an outflow reservoir. Mitochondrial respiration was not suppressed, and perfusate LDH activity was not increased, although lung wet weight increased as much as it did after the treatment described above. These results indicate that lung mitochondrial function is differentially affected by ET-1 and Lx, and they suggest that abnormalities in energy production by lung mitochondria are related to permeability edema.

Acute Disease↗
PubMed1998

Lead-induced alterations in retinal cGMP phosphodiesterase trigger calcium overload, mitochondrial dysfunction and rod photoreceptor apoptosis.

Lead exposure results in the selective apoptotic loss of rods and bipolar cells. During and following developmental lead exposure rod/retinal cGMP phosphodiesterase expression and activity are delayed in onset and decreased, [Ca2+] is elevated, and mitochondrial ATP synthesis is decreased. In vitro studies, using retinas incubated in Ca2+ and/or Pb2+, demonstrate that rods selectively die by apoptosis, retinal mitochondrial ATP synthesis is decreased, mitochondrial cytochrome c is released and caspase activity is increased. These results suggest that lead-induced rod and bipolar cell apoptosis is triggered by Ca2+ and Pb2+ overload due to altered cGMP phosphodiesterase activity and that mitochondrial alterations play a central role in this process.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Evidence against calcium as a mediator of mitochondrial dysfunction during apoptosis induced by arachidonic acid and other free fatty acids.

Apoptosis is often accompanied by activation of phospholipase A(2), causing release of free fatty acids (FFAs), which in turn are thought to contribute to the loss of mitochondrial transmembrane potential (Deltapsi(m)). In these experiments, we asked whether calcium plays a role as an intermediate in this process. A total of 14 FFAs were compared for their ability to cause loss of Deltapsi(m) and for their ability to affect levels of intracellular calcium. Among the FFAs, unsaturated FFAs tended to induce apoptosis while saturated FFAs did not. Arachidonic acid (AA) was most damaging, causing loss of Deltapsi(m) and cell death in 8-10 h while linoleic acid, gamma-linolenic acid, and docosapentaenoic also strongly induced apoptosis. Effects of the FFAs on levels of intracellular calcium were very different. Many caused strong calcium responses; however, the ability to induce a strong calcium response was not predictive of ability to induce apoptosis, and overall, we did not find a correlation between apoptosis and calcium induction. Also, verapamil and TMB-8 were able to block the calcium response, but these inhibitors did not prevent loss of Deltapsi(m), indicating that the calcium response is not necessary for FFA-induced loss of Deltapsi(m). In contrast, we found that cyclosporine A could inhibit the AA-induced loss of Deltapsi(m) with both whole cells and isolated mitochondria, confirming that the antimitochondrial effects of FFA can stem from direct effects on the mitochondrial permeability transition pore. Finally, we show that the strong apoptosis-inducing activity of AA may stem from its ability to selectively induce its own release.

Animals↗
PubMed1992

Mitochondrial dysfunction in the non-obstructed lobe of rat liver after selective biliary obstruction.

In order to elucidate the function of non-obstructed hepatic lobe during partial cholestasis, we have examined the effects of selective biliary obstruction on the mitochondrial energy transducing system in rat liver. The non-ligated lobe became hypertrophic after ligation of the bile ducts that drained 90% of the liver, and there was no increase in the level of serum bilirubin, alkaline phosphatase activity, or bile acids. However, mitochondrial oxidative phosphorylation function, specific enzymic activities of the oxidative phosphorylation complexes, and the subunit contents of these complexes were markedly decreased in the non-obstructed lobe at 4 weeks after the 90% biliary obstruction. There was no increase in the specific content of mitochondrial DNA. The mitochondrial energy transducing system in the non-obstructed lobes is not enhanced, but is significantly impaired during prolonged selective biliary obstruction, despite normal serum biochemical data and hypertrophy of the non-ligated lobe. These results imply early release of obstruction of cholestatic lobe, e.g. by biliary drainage, would be beneficial for maintaining the mitochondrial function in the non-cholestatic lobe.

Animals↗
PubMed2001

Nitric oxide prevents intestinal mitochondrial dysfunction induced by surgical stress.

BACKGROUND: The intestine is highly susceptible to free radical-induced damage and earlier work has shown that surgical stress induces generation of oxygen free radicals in enterocytes, resulting in intestinal damage along with changes in mitochondrial structure and function. Nitric oxide is an important mediator of gastrointestinal function and this study looked at the effect of nitric oxide on surgical stress-induced intestinal mitochondrial alterations. METHODS: Controls and rats pretreated with the nitric oxide donor L-arginine were subjected to surgical stress by opening the abdominal wall and handling the intestine. Enterocytes were isolated, mitochondria prepared and the protection offered by L-arginine against damage due to surgical stress was determined. Protection to structural as well as functional aspects of mitochondria was examined. RESULTS: Mild handling of the intestine affected the enterocyte mitochondrial structure as assessed by lipid composition and electron microscopy. Mitochondria were also functionally impaired with altered calcium flux and decreased respiratory control ratio. Pretreatment with the nitric oxide synthase substrate L-arginine prevented these damaging effects of surgical stress. Protection with arginine was abolished by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, indicating the role of nitric oxide. CONCLUSION: Surgical stress in the small intestine can affect enterocyte mitochondrial structure and function. These damaging effects can be prevented by nitric oxide, an important modulator of cellular function.

Animals↗
PubMed2001

Mitochondrial dysfunction by gamma-irradiation accompanies the induction of cytochrome P450 2E1 (CYP2E1) in rat liver.

Multiple biological effects are induced by ionizing radiation through dysfunction of cellular organelles, direct interaction with nucleic acids and production of free radical species. The expression of cytochrome P450s was assessed in the livers of 60Co gamma-irradiated rats. Three gray (G) of gamma-irradiation caused CYP2E1 induction with a 3.6-fold increase in the mRNA at 24 h, whereas the expression of CYP1A2 and CYP3A was not changed. Pharmacokinetics of chlorzoxazone, a specific substrate of CYP2E1, was studied in 3 G-irradiated rats. The area under the plasma concentration-time curve from time zero to infinity of 6-hydroxychlorzoxazone and the amount of 6-hydroxychlorzoxazone excreted in 8 h urine were both significantly greater than those in control rats. Hepatic CYP2E1 was not induced in rats exposed to 0.5-1 G of gamma-rays. Rats irradiated at 6-9 G accumulated doses of gamma-rays exhibited smaller increases in the mRNA due to liver injury than those irradiated at a single dose of 3 G gamma-rays. The plasma glucose and insulin levels were not altered in rats with 3 G of gamma-irradiation. As the exposure level of gamma-irradiation increased, the activity of hepatic aconitase, a key enzyme in energy metabolism in mitochondria, was 30-90% decreased. The amount of mitochondrial DNA per gram of wet liver was 50% decreased in rats exposed to 3 G of gamma-rays. These results demonstrated that gamma-ray irradiation at the exposure level inducing organelle dysfunction induced CYP2E1 in the liver, which might be associated with mitochondrial damage, but not with alterations in glucose or insulin levels.

Aconitate Hydratase↗