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PubMed1998

Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats.

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12-16 g ifosfamide/m2.day excreted thiodiglycolic acid ranging from 0.10 +/- 0.02 mmol on the first day of therapy, to a maximum of 3.27 +/- 0.15 mmol on the fourth day of ifosfamide infusion. This amounted to 5.4 +/- 0.2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days' continuous ifosfamide infusion. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-14C]palmitic acid by 55%, but affected neither the oxidation of [1-14C]octanoic acid, which is carnitine-independent, nor the oxidation of [1, 4-14C]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30 microM) inhibited oxidation of palmitic acid but not palmitoyl-L-carnitine in isolated rat liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid which may contribute to the adverse effects associated with ifosfamide chemotherapy.

Animals↗

PubMed1998

Effect of psychosine on mitochondrial function.

The effect of psychosine on the rate of respiration at different segments of the electron transport chain, respiratory control ratio and the efficiency of phosphorylation was studied. The transfer of electrons through site I, site II and site III was studied independently. The transfer through site I and site III was inhibited by psychosine, whereas the transfer through site II was not inhibited. Cardiolipin, which is essential for the electron transfer through site I and III, was implicated to be responsible for the inhibition of electron transfer by psychosine. Electron carriers of site II are not sensitive to cardiolipin, so psychosine could not inhibit the electron transfer through this site. The ADP/O ratio and respiratory control ratio were inhibited by psychosine showing that it has an uncoupler like effect. Mitochondria isolated from rat liver, kidney and brain behaved essentially the same way in their response to psychosine. Cytochrome c oxidase was significantly inhibited by psychosine and the degree of inhibition was almost same in mitochondria and sub mitochondrial particles. The preence of outer membrane in mitochondria did not make any difference with respect to the action of psychosine on electron transport chain. Psychosine interacts at site I and site III and a change in the lipid environment of the membrane is responsible for the mitochondrial dysfunctions induced by psychosine. This represents a possible mechanism for the destruction of cells in Gaucher's and Krabbe's disease.

Animals↗

PubMed2004

Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress.

Usnic acid, a lichen acid, is a compound found in crude medicines and dietary supplements, including Lipokinetix, a supplement marketed as a weight loss agent that caused hepatotoxicity and acute liver failure in patients. In this study, we examined the toxicity of usnic acid and assessed whether usnic acid may be contributing to hepatotoxicity caused by Lipokinetix. In primary cultured murine hepatocytes, usnic acid treatment (5 microM) resulted in 98% necrosis within 16 hr (no apoptosis was detected). Usnic acid treatment was associated with early inhibition and uncoupling of the electron transport chain in mitochondria of cultured hepatocytes. This inhibition of mitochondria by usnic acid corresponded with a fall in ATP levels in hepatocytes. In isolated liver mitochondria, usnic acid was observed to directly inhibit and uncouple oxidative phosphorylation. Oxidative stress appears to be central in usnic acid-induced hepatotoxicity based on the following findings: (1) pretreatment with antioxidants (butylated hydroxytoluene+Vitamin E) decreased usnic acid-induced necrosis by nearly 70%; (2) depletion of mitochondrial GSH with diethylmaleate increased susceptibility of hepatocytes to usnic acid; (3) usnic acid treatment was associated with increase free radical generation, measured using the fluorescent probe, dichlorodihydrofluorescin. The source of reactive oxygen species after usnic acid treatment include autoxidation of usnic acid and increased hydrogen peroxide generation by mitochondria caused by usnic acid inhibition of the respiratory chain, with the latter playing a more prominent role. Taken together, our results suggest that usnic acid is a strong hepatotoxic agent that triggers oxidative stress and disrupts the normal metabolic processes of cells. Usnic acid therefore may contribute to the hepatotoxic effects of Lipokinetix and its use in any supplement must come into question.

Adenosine Triphosphate↗

PubMed1996

New aspects of lactate metabolism: IGF-I and insulin regulate mitochondrial function in cultured brain cells during normoxia and hypoxia.

Using 13C nuclear magnetic resonance spectroscopy in combination with conventional biochemical techniques, effects of insulin and IGF-I on energy metabolism and cell viability were studied in cerebral cortical neurons, astrocytes and cocultures thereof during normoxia and hypoxia. Lactate dehydrogenase leakage was used to monitor the cytoprotective effects of IGF-I and insulin. Thus, during normoxia both peptides decreased LDH leakage from neurons. During hypoxia, however, this protection was only observed when insulin was present. Interestingly, neurons showed much less LDH leakage during hypoxia than astrocytes or cocultures. A possible explanation could be an increased glycolysis in neurons. Thus, lactate production and glucose consumption were increased severalfold in neurons during hypoxia whereas astrocytes and cocultures only showed a slight increase. Both insulin and IGF-I increased glucose metabolism during normoxia in astrocytes but not in neurons, whereas during hypoxia this increase was less pronounced. Using [1-13C]glucose it could be demonstrated that production of lactate from mitochondrial precursors was, in the presence of insulin or IGF-I, down regulated in astrocytes but increased in neurons during normoxia. This route for lactate production was not used during hypoxia and incorporation into the C-3 position of lactate approached the theoretical maximum of 50%.

Animals↗

PubMed2003

Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS.

Diclofenac is a non-steroidal anti-inflammatory drug that is widely used clinically but side effects associated with the administration of the drug have been reported. The apoptotic effect of the drug has been evaluated in human and rat hepatocytes. Apoptosis was observed after exposure to sub-cytotoxic concentrations of the drug, without overlapping with cell necrosis. Flow cytometric analysis revealed a time- and dose-dependent increase of apoptotic nuclei with sub-diploid DNA content. Caspase 8 and 9 mediate the cell-receptor and the mitochondria-initiated apoptotic pathways, respectively. Inhibition of both caspases prevented activation of downstream caspases, thus indicating that diclofenac at least activates caspase 3 and both effector caspases 8 and 9. The hierarchy of caspase activation by diclofenac was investigated. Analysis of kinetics revealed a simultaneous activation of these caspases that was maximal after 12 hr of exposure to the drug. Inhibitors of MPT, prevented the downstream activation of the caspase cascade, thus showing that diclofenac opened the mitochondrial pore. On the other hand, antioxidants were able to prevent caspase activation by diclofenac, revealing that oxidative stress at the mitochondrial level is in the root of MPT induction and caspase cascade activation. Caspase activation is not mediated by Bid cleavage, suggesting that the cell-receptor pathway seems not to be involved. However, a dose-dependent release of caspase 8 from the mitochondria was observed, indicating that caspase 8 can be processed independently of cell death receptors. Caspases 8 and 9 are very likely the apical caspases in diclofenac-induced apoptosis. In addition, an early dose-dependent increase of bclX(L) expression parallel to the generation of reactive oxygen species in the mitochondria was found. In conclusion, the mitochondrial pathway is very likely the only pathway involved in diclofenac-induced apoptosis, which was related to CYP-mediated metabolism of diclofenac, with the highest apoptotic effect produced by the metabolite 5OH-diclofenac.

Animals↗

PubMed1983

Inhibition of mitochondrial function is not the diuretic mechanism of ethacrynic acid in the dog.

Kidney metabolites were studied in five anesthetized dogs before and after 5 mg/kg i.v. of ethacrynic acid, followed by 3 mg X kg-1 X hr-1. This dose, which inhibits most of the reabsorption of sodium and chloride in the diluting segment, improved the energy state in biopsies from the outer medulla and caused an increase in ATP and a decrease in ADP and AMP levels and the lactate/pyruvate ratio. This was probably related to ongoing rapid metabolism in the control biopsies (with improved results after ethacrynic acid due to a primary reduction in an ATP requiring process) before they were completely frozen in liquid nitrogen. No changes occurred in ATP, ADP or phosphocreatine levels or the lactate/pyruvate ratio in cortical biopsies, which was in agreement with the previously shown lack of effect on proximal tubular reabsorption at this dosage of ethacrynic acid. These results indicate that the saluretic effect and parallel reduction in outer medullary metabolic rate with ethacrynic acid cannot be due to a direct inhibition of mitochondrial ATP production as suggested by others from in vitro experiments. The reduced rate of ATP production in vivo must be secondary to a reduced ATP demand.

Adenosine Triphosphate↗

PubMed2001

Altered mitochondrial function and overgeneration of reactive oxygen species precede the induction of apoptosis by 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine in p53-defective hepatocytes.

The mechanism of induction of apoptosis by the novel anti-cancer drug 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) was investigated in p53-defective SV40 immortalized rat hepatocytes (CWSV1). Exposure to 12 microM ET-18-OCH3 for 36 h induced apoptosis as determined using classical morphological features and agarose gel electrophoresis of genomic DNA. Increased levels of reactive oxygen species (ROS) were detected spectrophotometrically using a nitroblue tetrazolium (NBT) assay in cells treated with ET-18-OCH3. Both the increased generation of ROS and the induction of apoptosis were inhibited when cells were treated concurrently with ET-18-OCH3 in the presence of the antioxidant alpha-tocopherol. Similar results were achieved when cells were switched acutely to choline-deficient (CD) medium in the presence of the antioxidant. The possible role of mitochondria in the generation of ROS was investigated. Both ET-18-OCH3 and CD decreased the phosphatidylcholine (PC) content of mitochondrial and associated membranes, which correlated with depolarization of the mitochondrial membrane as analyzed using 5,5',6,6'-tetramethylbenzimidazolcarbocyanine iodide (JC-1), a sensitive probe of mitochondrial membrane potential. Rotenone, an inhibitor of the mitochondrial electron transport chain, significantly reduced the intracellular level of ROS and prevented mitochondrial membrane depolarization, correlating with a reduction of apoptosis in response to either ET-18-OCH3 or CD. Taken together, these results suggest that the form of p53-independent apoptosis induced by ET-18-OCH3 is mediated by alterations in mitochondrial membrane PC, a loss of mitochondrial membrane potential, and the release of ROS, resulting in completion of apoptosis.

Animals↗

PubMed1991

[Post-traumatic jaundice--its mechanism from a view point of hepatic mitochondrial function].

It has been proposed that post-traumatic jaundice was the result of increased hemolysis, absorption of hematoma, effects of drugs, and so on. We considered that hepatic impairment in the bilirubin metabolism as a result of hepatic hypoperfusion might also be an important factor of the jaundice. Patients who developed jaundice after trauma were divided into two groups according to the maximum total bilirubin level; groups H (greater than 8 mg/dl) and L (less than 5 mg/dl). Severity of shock, levels of serum hepatic enzyme, and blood ketone body ratio were compared between the groups. Minimum systolic pressure, H 58, L 82 mmHg (p = 0.003); duration of shock (less than 80 mmHg), H 225, L 20 min (p less than 0.001); blood transfusion, H 9188, L 2914 ml (p less than 0.001); direct/total bilirubin, H 0.66, L 0.43 (p less than 0.001). Although no significant difference was noted in serum hepatic enzyme levels, blood ketone body ratios were significantly lower in group H throughout the first week. From these facts, it is considered that an impairment in the most energy requiring process of bilirubin metabolism, excretion of conjugated bilirubin from cytosol to capillary bile duct, due to post-traumatic hepatic mitochondrial dysfunction, followed by the reabsorption of conjugated bilirubin into the blood stream, would be one of factors of post-traumatic jaundice.

Bilirubin↗

PubMed2001

Restoration of mitochondrial function reverses developmental neuronal death in vitro.

In a previous study characterizing morphological and functional features of cell death in trophically deprived chick ciliary ganglion neurons (Pena and Pilar [2000] J. Comp. Neurol. 424:377-396), we hypothesized that early cell death events might be targets for reversal, allowing for rescue of dying neurons. To test this hypothesis, ciliary ganglion (CG) neurons were cultured with or without trophic support (choroid, iris, and pigment epithelium soluble extract [CIPE]), or without trophic support for 11 or 18 hours and then exposed to trophic support. Prior to and at the onset of cell death commitment (11 hours) CIPE-deprived neurons exhibited increased membrane permeability, blebbing, cytoplasmic vacuolization, swollen mitochondria, low adenosine triphosphate levels, and release of cytochrome c from mitochondria. CIPE readdition at 11 hours reversed these changes. Between 11 and 18 hours, irreversible DNA fragmentation increased in CIPE-deprived neurons. Cyclosporin A and bongkrekic acid (inhibitors of mitochondrial transition permeability pores) prevented membrane permeability increases and delayed the progression to death in trophically deprived neurons by 12 hours; however, by 48 hours all neurons had died. BOC-Asp-CH2F (BAF), a pan-caspase inhibitor, did not prevent early events of cell death including increased membrane permeability and Cyto c release, but it inhibited DNA fragmentation and prolonged neuronal survival to 48 hours. We conclude that mitochondria changes occur early, prior to commitment and that the suppression of these changes can prevent all the downstream events of death, whereas caspase inhibitors have no effect on the early mitochondria/plasma membrane changes. Mitochondria thus play a critical role in the transition from reversible to irreversible commitment to developmental neuronal death. Furthermore, neuronal death is brought about by activation of one of two distinct pathways, one localized in mitochondria and the other dependent on activation of caspases.

Adenosine Triphosphate↗

PubMed2000

Hyperthermia impairs liver mitochondrial function in vitro.

The effects of temperature on the relationships among the rates of pyruvate carboxylation, O(2) uptake (J(o)), oxidative phosphorylation (J(p)), and the free energy of ATP hydrolysis (G(p)) were studied in liver mitochondria isolated from 250-g female rats. Pyruvate carboxylation was evaluated at 37, 40, and 43 degrees C. In disrupted mitochondria, pyruvate carboxylase maximal reaction velocity increased from 37 to 43 degrees C with an apparent Q(10) of 2.25. A reduction in ATP/ADP ratio decreased enzyme activity at all three temperatures. In contrast, in intact mitochondria, increasing temperature failed to increase pyruvate carboxylation (malate + citrate accumulation) but did result in increased J(o) and decreased extramitochondrial G(p). J(p) was studied in respiring mitochondria at 37 and 43 degrees C at various fractions of state 3 respiration, elicited with a glucose + hexokinase ADP-regenerating system. The relationship between J(o) and G(p) was similar at both temperatures. However, hyperthermia (43 degrees C) reduced the J(p)/J(o) ratio, resulting in lower G(p) for a given J(p). Fluorescent measurements of membrane phospholipid polarization revealed a transition in membrane order between 40 and 43 degrees C, a finding consistent with increased membrane proton conductance. It is concluded that hyperthermia augments nonspecific proton leaking across the inner mitochondrial membrane, and the resultant degraded energy state offsets temperature stimulation of pyruvate carboxylase. As a consequence, at high temperatures approaching 43 degrees C, the pyruvate carboxylation rate of intact liver mitochondria may fail to exhibit a Q(10) effect.

Adenosine Triphosphate↗

PubMed2001

Diet restriction plays an important role in the alterations of heart mitochondrial function following exposure of young rats to chronic hypoxia.

Male Wistar rats aged 4 weeks, were subjected to hypobaric hypoxia (barometric pressure 505 hPa, PI,O2 106 hPa) or to diet restriction (reproducing the effect of hypoxia-induced anorexia) for 4 weeks. Each group (control, hypoxic, pair-fed, n = 16), was divided into two sub-groups housed individually in either normal cages or cages with running wheels allowing evaluation of voluntary activity (n = 8 each). The skinned-fibre technique was used to evaluate the functional properties of myofibrillar mitochondria from right and left ventricles in situ. The oxidative fibres from the soleus and diaphragm muscles were also investigated for comparison. Analysis of variance did not detect any significant effect of voluntary running activity. With calorie restriction, the maximal respiratory rate (Vmax) in the presence of 1 mM adenosine 5'-diphosphate (ADP) in myocardial fibres fell significantly (by about 25%) but was unchanged in skeletal myocytes. Following hypoxia, Vmax in myocardial fibres increased by 25% compared with the calorie restricted group and in soleus and diaphragm muscle fibres by about 30% compared with control. In myocardial fibres of control rats, creatine (20 mM) increased the sub-maximal respiratory rate by 80% in the presence of 0.1 mM ADP. Under calorie restriction or hypoxia the stimulatory effect was significantly reduced to 34-56%. This alteration was due to a decrease in the apparent Michaelis-Menten constant (Km) of mitochondrial respiration for ADP evaluated in the absence of creatine, while the Km in presence of creatine 20 mM was unchanged. In conclusion, reduced food intake decreased the oxidative capacity (Vmax) and the apparent Km for ADP of mitochondria in both left and right ventricles. Chronic hypoxia per se was responsible for an increase in the oxidative capacity of all oxidative muscles but did not exert significant effects on the control of respiration by ADP and creatine in myocardium.

Adenosine Diphosphate↗

PubMed1985

Prolonged cardiac arrest and resuscitation in dogs: brain mitochondrial function with different artificial perfusion methods.

Clinical techniques for artificial perfusion have not previously been examined directly for their effects on brain high-energy metabolism. Our study involved 24 large mongrel dogs that were anesthetized, instrumented for central venous intravenous access, and subjected to craniotomy to expose the dura and underlying parietal cortex. The animals were divided into the following six experimental groups of four animals each: nonischemic controls; 15-minute cardiac arrest without resuscitation; 45-minute cardiac arrest without resuscitation; 15-minute cardiac arrest plus 30 minutes resuscitation with conventional cardiopulmonary resuscitation (CPR); 15-minute cardiac arrest plus 30 minutes resuscitation with interposed abdominal compression (IAC) CPR; and 15-minute cardiac arrest plus 30 minutes resuscitation with internal cardiac massage. Cardiac arrest was induced by central venous injection of KCl 0.6 mEq/kg, and it was confirmed by continuous ECG monitoring. The three active resuscitation models included administration of NaHCO3 and epinephrine, but no attempt was made to restart the heart by defibrillation during resuscitation. At the indicated time in each group, a 4- to 5-g sample of brain was removed through the craniotomy, immediately cooled to 0 C and processed for isolation of mitochondria. The mitochondria were studied for their content of superoxide dismutase and for quantitative oxygen consumption with glutamate/malate substrate during resting and ADP-stimulated respiration. Our results show a significant drop in brain mitochondrial superoxide dismutase activity during the first 15 minutes of cardiac arrest. There is minimal injury to brain mitochondrial oxygen consumption during both 15 and 45 minutes of complete ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Assessment of ram sperm mitochondrial function by quantitative determination of sperm rhodamine 123 accumulation.

A simple procedure is described for determining the functional state of ram sperm mitochondria by quantitative measurement of sperm rhodamine 123 (R 123) accumulation. Sperm were incubated with 1 microgram/ml R 123, and the accumulated R 123 was measured fluorimetrically after release from washed sperm by detergent lysis. Ram sperm R 123 uptake was maximal after 30 min of incubation and responded to changes in both sperm (P < 0.01) and R 123 (P < 0.01) concentration. There was a linear relationship (r = 0.98) between R 123 uptake and the proportion of cold-shocked sperm present in a sperm sample. R 123 uptake was unaffected by 20 mM 2-deoxyglucose or by 10 mM malonate (the latter being sufficient to reduce O2 uptake; P < 0.01). R 123 accumulation in ram sperm was reduced by 6 mg/ml sodium pentobarbitone (P < 0.05), by 1 microM 2,4-dinitrophenol (P < 0.01), and by 0.05% Triton X-100 (P < 0.01). It is concluded that quantitative estimation of R 123 uptake complements oxygen uptake in detecting mitochondrial dysfunction in ram sperm. While it is largely unaffected by inhibition of glycolysis, and is less sensitive than oxygen uptake to trichloroacetic acid cycle inhibition, R 123 uptake is sensitive to factors directly reducing the mitochondrial membrane potential of ram sperm. It may therefore by useful in the evaluation of the effects of such membrane-mediated injuries as cold shock and freezing damage on ram sperm mitochondria.

2,4-Dinitrophenol↗

PubMed2002

Retortamonad flagellates are closely related to diplomonads--implications for the history of mitochondrial function in eukaryote evolution.

We present the first molecular phylogenetic examination of the evolutionary position of retortamonads, a group of mitochondrion-lacking flagellates usually found as commensals of the intestinal tracts of vertebrates. Our phylogenies include small subunit ribosomal gene sequences from six retortamonad isolates-four from mammals and two from amphibians. All six sequences were highly similar (95%-99%), with those from mammals being almost identical to each other. All phylogenetic methods utilized unequivocally placed retortamonads with another amitochondriate group, the diplomonads. Surprisingly, all methods weakly supported a position for retortamonads cladistically within diplomonads, as the sister group to Giardia. This position would conflict with a single origin and uniform retention of the doubled-cell organization displayed by most diplomonads, but not by retortamonads. Diplomonad monophyly was not rejected by Shimodaira-Hasegawa, Kishino-Hasegawa, and expected likelihood weights methods but was marginally rejected by parametric bootstrapping. Analyses with additional phylogenetic markers are needed to test this controversial branching order within the retortamonad + diplomonad clade. Nevertheless, the robust phylogenetic association between diplomonads and retortamonads suggests that they share an amitochondriate ancestor. Because strong evidence indicates that diplomonads have secondarily lost their mitochondria (rather than being ancestrally amitochondriate), our results imply that retortamonads are also secondarily amitochondriate. Of the various groups of eukaryotes originally suggested to be primitively amitochondriate under the archezoa hypothesis, all have now been found to have physical or genetic mitochondrial relics (or both) or form a robust clade with an organism with such a relic.

Animals↗

PubMed2003

Hprt(CAG)146 mice: age of onset of behavioral abnormalities, time course of neuronal intranuclear inclusion accumulation, neurotransmitter marker alterations, mitochondrial function markers, and susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We reported previously a model of polyglutamine repeat disorders with insertion of 146 CAG repeats into the murine hypoxanthine phosphoribosyl transferase locus (Hprt(CAG)146; Ordway et al. [1997] Cell 91:753-763), which does not normally contain polyglutamine repeats. These mice develop an adult-onset neurologic phenotype of incoordination, involuntary limb clasping, seizures, and premature death. Histologic analysis demonstrates widespread ubiquinated neuronal intranuclear inclusions (NIIs). We now report characterization of the age of onset of behavioral abnormalities, correlated with the time course of occurrence of NIIs in several brain regions, and the occurrence of NIIs in non-neuronal tissues. Onset of behavioral abnormalities occurred at approximately 22 weeks of age. There was variable time course of expression of NIIs in several brain regions. Assessment of several non-neuronal tissues revealed nuclear inclusions in hepatocytes and choroid plexus epithelium. Gamma-aminobutyric acid (GABA)/benzodiazepine receptors, dopamine D1-like and D2-like receptors, and type 2 vesicular monoamine transporter (VMAT2) binding sites were assayed before and after the onset of behavioral abnormalities. GABA/benzodiazepine receptors were unchanged either before or after the onset of behavioral abnormalities in any region analyzed, whereas striatal D1-like and D2-like receptors were diminished after but not before the onset of symptoms. Dorsal striatal VMAT2 binding sites were decreased before the onset of behavioral changes. Mitochondrial electron transport chain components were assayed with histochemical methods before and after the onset of behavioral changes. There was no change in behaviorally presymptomatic or symptomatic animals. Hprt(CAG)146 mice did not exhibit increased susceptibility to the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Hprt(CAG)146 mice are a useful model for studying polyglutamine repeat disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1994

Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease.

Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone-sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Contractile performance, mitochondrial function and blood flow distribution in porcine heart with induced coronary collateral circulation.

Progressive stenosis of the proximal left anterior descending coronary artery in young pigs was surgically induced over eight weeks and was accompanied by the development of a coronary collateral circulation originating from the right coronary artery. The antero-apical left ventricular myocardium dependent on this induced collateral blood supply became hypokinetic compared with the other regions of the left ventricle in the same hearts, and compared with the same region in different hearts, where the native circulation exists. Regional myocardial mechanics determined as fractional systolic shortening was 12.5 +/- 1.5% in normal regions, 0.7 +/- 2.4% in collateral-dependent myocardium, and in acutely ischemic myocardium was -2.0 +/- 1.3%, indicative of systolic lengthening. The rate of state 3 respiration of isolated mitochondria was depressed by 20% in collateral regions and by 64% in acutely ischemic regions relative to values obtained in mitochondria from respective normal myocardium (300 natoms of oxygen/min/mg mitochondria protein). Regional myocardial blood flow determined by 15 mu radionuclide labelled spheres revealed subendocardial hypoperfusion of 0.34 +/- 0.11 ml/min/g tissue in the collateral-dependent regions compared to 1.06 +/- 0.26 ml/min/g tissue in the normal regions. Transmural ischemia was observed (less than 0.10 ml/min/g tissue) in regions subjected to acute coronary artery ligation. Light microscopy revealed patchy fibrotic lesions predominately associated with the subendocardial half of the collateral dependent myocardial wall. Accordingly, the hypokinesia of collateral-dependent myocardium is more likely the result of blood flow abnormalities and loss of contractile elements than from mitochondrial dysfunction.

Animals↗

PubMed1996

Inhibition of mitochondrial function in isolated rate liver mitochondria by azole antifungals.

Ketoconazole is an imidazole oral antifungal agent with a broad spectrum of activity. Ketoconazole has been reported to cause liver damage, but the mechanism is unknown. However, ketoconazole and a related rug, miconazole, have been shown to have inhibitory effects on oxidative phosphorylation in fungi. Fluconazole, another orally administered antifungal azole, has also been reported to cause liver damage despite its supposedly low toxicity profile. The primary objective of this study was to evaluate the metabolic integrity of adult rat liver mitochondria after exposure to ketoconazole, miconazole, fluconazole, and the deacetylated metabolite of ketoconazole by measuring ADP-dependent oxygen uptake polarographically and succinate dehydrogenase activity spectrophotometrically. Ketoconazole, N-deacetyl ketoconazole, and miconazole inhibited glutamate-malate oxidation in a dose-dependent manner such that the 50% inhibitory concentration (I50) was 32,300, and 110 microM, respectively. In addition, the effect of ketoconazole, miconazole, and fluconazole on phosphorylation coupled to the oxidation of pyruvate/malate, ornithine/malate, arginine/malate, and succinate was evaluated. The results demonstrated that ketoconazole and miconazole produced a dose-dependent inhibition of NADH oxidase in which ketoconazole was the most potent inhibitor. Fluconazole had minimal inhibitory effects on NADH oxidase and succinate dehydrogenase, whereas higher concentrations of ketoconazole were required to inhibit the activity of succinate dehydrogenase. N-deacetylated ketoconazole inhibited succinate dehydrogenase with an I50 of 350 microM. In addition, the reduction of ferricyanide by succinate catalyzed by succinate dehydrogenase demonstrated that ketoconazole caused a dose-dependent inhibition of succinate activity (I50 of 74 microM). In summary, ketoconazole appears to be the more potent mitochondrial inhibitor of the azoles studied; complex I of the respiratory chain is the apparent target of the drug's action.

Animals↗