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PubMed1989

Effect of 3-(2,2,2-trimethylhydrazinium) propionate, gamma-butyrobetaine hydroxylase inhibitor, on isoproterenol-induced mitochondrial dysfunction.

The present study was designed to investigate whether or not reduction of carnitine content could protect isoproterenol (ISP)-induced myocardial injury using 3-(2,2,2-trimethylhydrazinium) propionate (TMHP), gamma-butyrobetaine hydroxylase inhibitor. Rats were divided into 4 groups; the control group: untreated, the TMHP-1 group: TMHP (100 mg/kg) was administered intraperitoneally, and ISP (10 mg/kg) was administered subcutaneously on the following day, the TMHP-7 group: TMHP (100 mg/kg) for 7 successive days, and ISP (10 mg/kg) on the eighth day, the ISP group: ISP (10 mg/kg) was administered. Rats were cervically dislocated 15 hours after ISP administration, and heart mitochondrial electron-transport activity (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) were measured enzymatically. Activity of succinate-cytochrome c reductase was not affected significantly by ISP, however, NADH-cytochrome c reductase and cytochrome c oxidase were significantly reduced in the ISP and TMHP groups. Administration with TMHP for 7 successive days lessened the reduction of the activities. Mitochondrial electron-transport system plays an important role in cellular energy transduction. These results suggested that mitochondrial dysfunction induced by ISP is related to carnitine-dependent fatty acid metabolism and that TMHP reduces the myocardial injury.

Animals↗
PubMed1999

Apoptotic changes precede mitochondrial dysfunction in red cell-type pyruvate kinase mutant mouse erythroleukemia cell lines.

Two erythroleukemia cell lines have been established from the splenic lesions of red blood cell-type pyruvate kinase (R-PK) activity-deficient mice of CBA/N origin infected with a polycythemic strain of Friend leukemia virus complex (FVp). Ten to 30% of the cells of these cell lines undergo apoptotic changes in routine passage, as shown by nuclear fragmentation, DNA laddering, DNA content (propidium iodide (PI) staining), and annexin V binding assay. In these cells, however, although adenosine 5'-triphosphate (ATP) levels were lower than in the control cells, the mitochondrial inner transmembrane potential (delta psi m), detected by rhodamine 123 (R123) and diSC3(5) staining, remained unchanged until the final stage of apoptosis. No evidence was obtained to relate this finding to R-PK mutation due to difficulty in cloning stable, conditionally inducible R-PK gene transfectants. However, low delta psi m in the apoptotic cell population of the control T3-K-1 (K-1) and T3-CI-2-0 (2-0) Friend erythroleukemia cells supports a possible relationship, as do results obtained in two Friend erythroleukemia cells recently isolated from normal CBA/N mice. These cell lines are expected to be useful for clarifying both the primary apoptotic changes independent of mitochondrial dysfunction and the PK-isozyme changes during erythrodifferentiation, for example, the decreased muscle type 2 (M2) PK level. Modification of growth signals in these cell lines may modulate differentiation and/or apoptosis and allow further elucidation of the signaling networks.

Adenosine Triphosphate↗
PubMed2003

Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices.

Brain ischemia is frequently associated with oxidative stress in the reperfusion period. It is known that noradrenaline (NA) is released in excess under energy deprivation by the sodium-dependent reversal of the monoamine carrier. However, it is not known how oxidative stress affects NA release in the brain alone or in combination with energy deprivation. As a model of oxidative stress, the effect of H(2)O(2) (0.1-1.5 mM) perfusion was investigated in superfused rat hippocampal slices. It elicited a dose-dependent elevation of the release of [(3)H]NA and its tritiated metabolites as well as a simultaneous drop in the tissue energy charge. Mitochondrial inhibitors, i.e. rotenone (10 microM), and oligomycin (10 microM) in combination, also decreased the energy charge, but they had only a mild effect on [(3)H]NA release. However, when H(2)O(2) was added together with oligomycin and rotenone their effect on [(3)H]NA release was greatly exacerbated. H(2)O(2) and mitochondrial inhibitors also induced an increase in [Na(+)](i) in isolated nerve terminals, and their effect was additive. The effect of H(2)O(2) on tritium release was temperature-dependent. It was also attenuated by the glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (30 microM) and (+/-)-2-amino-5-phosphonopentanoic acid (10 microM), by the nitric oxide synthase inhibitors, N omega-nitro-L-arginine methyl ester (100 microM), or 7-nitroindazole (50 microM) and by the vesicular uptake inhibitor tetrabenazine (1 microM). Our results suggest that oxidative stress releases glutamate followed by activation of postsynaptic ionotropic glutamate receptors that trigger nitric oxide production and results in a flood of NA from cytoplasmic stores. The massive elevation of extracellular NA under conditions of oxidative stress combined with mitochondrial dysfunction may provide an additional source of highly reactive free radicals thus initiating a self-amplifying cycle leading to neuronal degeneration.

Animals↗
PubMed2002

Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.

Adult↗
PubMed2003

[Na+ overload-induced mitochondrial dysfunction in myocardial ischemia/reperfusion injury].

An accumulation of Na+ is induced in the ischemic myocardium, which is so-called "Na+ overload". The exact role of Na+ overload in the genesis of myocardial ischemia/reperfusion injury remains unclear except for the role as a driving force of Ca2+ overload in the reperfused myocardium. Excessive activation of Na+/H+ exchanger (NHE) and Na+ channels may contribute to Na+ influx into the ischemic myocardium, resulting in sodium overload under ischemic conditions. A decrease in energy-producing ability of mitochondria in the ischemic myocardium is also observed in an ischemic duration-dependent manner. Attenuation of Na+ overload by an NHE inhibitor or a Na+ channel blocker preserved mitochondrial energy production in the ischemic myocardium and enhanced post-ischemic contractile recovery. To mimic Na+ overload in the ischemic myocardium, isolated mitochondria were incubated with sodium lactate, a possible end product of anaerobic glycolysis. Sodium lactate induced an irreversible reduction in the mitochondrial energy production. The mitochondrial damage induced by sodium lactate was not attenuated by the NHE inhibitor or the Na+ channel blocker, suggesting that these agents may indirectly preserve mitochondrial function in the ischemic myocardium. Taken together, Na+ overload in the ischemic myocardium may induce mitochondrial dysfunction, leading to contractile failure of the reperfused myocardium.

Humans↗
PubMed2003

Oxidized LDL promotes peroxide-mediated mitochondrial dysfunction and cell death in human macrophages: a caspase-3-independent pathway.

Several studies suggest that macrophage death and subsequent lysis contribute to the development of advanced atherosclerotic lesions. Although oxidized LDL (OxLDL) is thought to contribute to lesion formation and induces macrophage apoptosis, the mechanisms underlying macrophage lysis have not been well defined. To determine if induction of apoptosis in human macrophages also promotes cell lysis, we studied caspase-3 activation by OxLDL and activating anti-Fas antibodies. We found that Fas-induced activation of caspase-3 does not promote macrophage lysis and caspase-3 activation is not required for OxLDL-induced macrophage lysis. OxLDL induces the formation of peroxides, but not superoxide, and decreases mitochondrial membrane potential. Scavengers of peroxyl radicals restore mitochondrial membrane potential and prevent macrophage lysis, implicating peroxyl radicals in both mitochondrial dysfunction and macrophage lysis induced by OxLDL. We conclude that macrophage death induced by OxLDL results in cell lysis, but it does not require activation of Fas or caspase-3. The full text of this article is available at http://www.circresaha.org.

Antibodies↗
PubMed1999

Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis.

Hereditary tyrosinemia type I is the most severe metabolic disease of the tyrosine catabolic pathway mainly affecting the liver. It is caused by deficiency of fumarylacetoacetate hydrolase, which prevents degradation of the toxic metabolite fumarylacetoacetate (FAA). We report here that FAA induces common effects (i.e., cell cycle arrest and apoptosis) in both human (HepG2) and rodent (Chinese hamster V79) cells, effects that seem to be temporally related. Both the antiproliferative and apoptosis-inducing activities of FAA are dose dependent and enhanced by glutathione (GSH) depletion with L-buthionine-(S,R)-sulfoximine (BSO). Short treatment (2 h) with 35 microM FAA/+BSO or 100 microM FAA/-BSO induced a transient cell cycle arrest at the G2/M transition (20% and 37%, respectively) 24 h post-treatment. In cells treated with 100 microM FAA/-BSO, an inactivation, followed by a rapid over-induction of cyclin B-dependent kinase occurred, which peaked 24 h post-treatment. Maximum levels of caspase-1 and caspase-3 activation were detected at 3 h and 32 h, respectively, whereas release of mitochondrial cytochrome c was maximal at 24-32 h post-treatment. The G2/M peak declined 24 h later, concomitantly with the appearance of a sub-G1, apoptotic population showing typical nucleosomal-sized DNA fragmentation and reduced mitochondrial transmembrane potential (Deltapsi(m)). These events were prevented by the general caspase inhibitor z-VAD-fmk, whereas G2/M arrest and subsequent apoptosis were abolished by GSH-monoethylester or N-acetylcysteine. Other tyrosine metabolites, maleylacetoacetate and succinylacetone, had no antiproliferative effects and induced only very low levels of apoptosis. These results suggest a modulator role of GSH in FAA-induced cell cycle disturbance and apoptosis where activation of cyclin B-dependent kinase and caspase-1 are early events preceding mitochondrial cytochrome c release, caspase-3 activation, and Deltapsi(m) loss. -Jorquera, R., Tanguay, R. M. Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis.

Acetoacetates↗
PubMed2003

Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction.

Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous adverse effects, including potentially life-threatening pulmonary fibrosis. The current study was undertaken to investigate potential protective mechanisms of vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three weeks after intratracheal administration of AM (1.83 micromol), increased pulmonary hydroxyproline content and histological damage were observed, indicative of fibrosis. These effects were preceded by increased pulmonary levels of transforming growth factor (TGF)-beta1 mRNA at 1 week post-AM, which remained elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in rapid pulmonary accumulation of the vitamin, and prevention of AM-induced increases in TGF-beta1, hydroxyproline, and histological damage. Although dietary supplementation also markedly elevated lung mitochondrial vitamin E content, it did not attenuate AM-induced inhibition of mitochondrial respiration or disruption of mitochondrial membrane potential in vitro, or lung mitochondrial respiratory inhibition resulting from in vivo AM administration. These results suggest that vitamin E reduces the extent of pulmonary damage after AM administration via down-regulating TGF-beta1 overexpression but that it does not modify AM-induced mitochondrial dysfunction, a potential initiating event in AIPT.

Amiodarone↗
PubMed1999

Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration.

Synapses are often located at great distances from the cell body and so must be capable of transducing signals into both local and distant responses. Although progress has been made in understanding biochemical cascades involved in neuronal death during development of the nervous system and in various neurodegenerative disorders, it is not known whether such cascades function locally in synaptic compartments. Prostate apoptosis response-4 (Par-4) is a leucine zipper and death domain-containing protein that plays a role in neuronal apoptosis. We now report that Par-4 levels are rapidly increased in cortical synaptosomes and in dendrites of hippocampal neurons in culture and in vivo, following exposure to apoptotic or excitotoxic insults. Par-4 expression is regulated at the translational level within synaptic compartments. Par-4 antisense treatment suppressed mitochondrial dysfunction and caspase activation in synaptosomes and prevented death of cultured hippocampal neurons following exposure to excitotoxic and apoptotic insults. Local translational regulation of death-related proteins in synaptic compartments may play a role in programmed cell death, adaptive remodeling of synapses, and neurodegenerative disorders.

Animals↗
PubMed2002

Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion.

We reported previously that acetaminophen overdose interrupts the signaling pathway of Fas receptor-mediated apoptosis. The aim of our study was to investigate the mechanism of this effect. Male C3Heb/FeJ mice received a single dose of acetaminophen (300 mg/kg ip) and/or anti-Fas antibody Jo-2 (0.6 mg/kg iv). Some animals were treated with allopurinol (100 mg/kg po) 18 and 1 h before acetaminophen injection. After 90 min of Jo treatment, there was processing of procaspase-3 and a significant increase in liver caspase-3 activity, which is consistent with apoptotic cell death. Treatment with acetaminophen 2.5 h before Jo inhibited the increase in hepatic caspase-3 activity by preventing the processing of the proenzyme. When administered alone, acetaminophen did not induce caspase-3 activation but caused significant liver injury. Acetaminophen treatment alone caused mitochondrial cytochrome c release, depletion of the hepatic ATP content by 55%, and a 10-fold increase in mitochondrial glutathione disulfide levels. Pretreatment with allopurinol prevented the mitochondrial oxidant stress and liver injury due to acetaminophen toxicity but had no effect on Jo-mediated apoptosis. Allopurinol did not affect the initial glutathione depletion after acetaminophen. However, allopurinol restored the sensitivity of hepatocytes to Fas receptor signaling in acetaminophen-treated animals. Histochemical evaluation of DNA fragmentation with the TUNEL assay showed that acetaminophen eliminated Fas receptor-mediated apoptosis in all hepatocytes not just in the damaged cells of the centrilobular area. Our data suggest that acetaminophen-induced mitochondrial dysfunction and not the initial glutathione depletion is responsible for the interruption of Fas receptor-mediated apoptotic signaling in hepatocytes.

Acetaminophen↗
PubMed2003

mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish.

Polymorphism of the mtDNA genome has been implicated as playing a role in the development and pathogenesis of Parkinson's disease (PD). A PCR-RFLP methodology was employed to generate genetic haplotypes for a cohort of 90 PD sufferers. No association was observed between the various mtDNA haplotypes observed and PD in comparison to healthy aged controls. The longevity-associated European J haplogroup and T haplogroup were identified and were both found to be in tight linkage with the mt4216C polymorphism. The mt4216C variant was observed at a significantly increased frequency in the PD cases (28%) in comparison to the healthy aged controls (15%; p=0.014). However, when the frequency of the mt4216C variant was examined in a cohort of 200 young controls (18-45 years) a similar frequency to the PD cases (25%) was observed. The frequencies obtained for the two branches of the J haplogroup (J1 and J2) and the T haplogroup in the cohort of PD subjects also reflected those observed for the young controls used in the previous longevity study. These findings lead one to postulate that the mt4216C variant, in linkage with the mtDNA TJ cluster, may influence mitochondrial dysfunction, resulting in an increased risk of PD.

Adult↗
PubMed2002

[The use of positron emission tomography for noninvasive diagnosis of mitochondrial dysfunction and assessment of myocardial compensatory reserve in children with cardiomyopathies].

BACKGROUND: Recent experimental and clinical studies have shown that cardiomyopathy (CMP) can be associated with disorders of oxidative metabolism in cardiomyocyte mitochondria. These disorders are connected with deficit of enzymes and complexes of electron transfer chain, and can constitute pathogenetic base of the disease. AIM. To study myocardial metabolism in children with cardiomyopathies using positron emission tomography (PET). METHODS: PET studies were carried out in 17 patients (pts.) aged 3-13 years (mean age 7,5-/+3,1) with CMP: hypertrophic (HCMP, n=4), dilated (DCMP, n=9), after radical correction of tetralogy of Fallot (TF, n=4). The dynamic study with [1-11C]-acetate was performed for evaluation of Krebs cycle activity. Rate constant (kmono) and [11C]-activity elimination half-time (T1/2) were calculated using myocardial time-activity curve. Myocardial perfusion was assessed with [13N]-ammonia, glucose metabolism - with [18F]-fluorodeoxyglucose. RESULTS: Patients with HCMP: left ventricular (LV) perfusion was normal, Krebs cycle activity - decreased; glucose utilization was increased in comparison with normal level in 2, and was normal in 2 other children. Patients with DCMP: LV perfusion was normal; Krebs cycle activity in LV was decreased in 6 and normal - in 3 pts. Overall 2 pts. with CMP had focal perfusion defects. More pronounced decrease of Krebs cycle activity in these regions compared with other LV parts implied development of ischemic injuries. Decrease of glucose utilization in these fields indicated that the injuries were irreversible. Patients with TF: 3 pts. had normal perfusion and Krebs cycle activity; 1 patient with severe hemodynamic disorders had decreased perfusion, glycolysis and Krebs cycle activity in both ventricles indicative of the presence of myocardial dystrophic changes. CONCLUSION: Despite normal perfusion children with cardiomyopathy had decreased Krebs cycle activity (mitochondrial dysfunction). Decrease in oxidative metabolism could be compensated by increased glycolysis.

Cardiomyopathies↗
PubMed2001

Amphotericin B potentiates the activation of inducible nitric oxide synthase and causes nitric oxide-dependent mitochondrial dysfunction in cytokine-treated rodent astrocytes.

Because the neurotoxic effects of the antifungal drug amphotericin B (AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes. AMB caused a dose-dependent increase of NO generation in interferon-gamma (IFN-gamma)-stimulated rat and mouse astrocytes, as well as in IFN-gamma + tumor necrosis factor-alpha (TNF-alpha)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor IRF-1. The activation of transcription factor NF-kappaB was apparently required for AMB-induced iNOS mRNA expression, as the latter was abolished by NF-kappaB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-gamma + AMB treatment led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity toward IFN-gamma-stimulated astrocytes was dependent on both AMB and NO action, since AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial dysfunction. These results suggest that the enhancement of cytokine-induced iNOS activation in astrocytes and the subsequent release of high amounts of NO might be at least partly responsible for AMB neurotoxicity.

Amphotericin B↗
PubMed2002

Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat.

Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and alpha-ketoglutarate dehydrogenase (alphaKDH) activity were both significantly (P<0.05) reduced by approximately 20% in the first 16-44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention.

Animals↗
PubMed1998

Mitochondrial dysfunction of human muscle in chronic alcoholism detected by using 31P-magnetic resonance spectroscopy and near-infrared light absorption.

We previously examined the effect of alcohol on muscle energy metabolism in chronic alcoholics by using 31P-magnetic resonance spectroscopy. Measurements of intracellular pH and PCr index [PCr/(PCr + Pi)] during resting, hand grasping, and recovery in the left flexor digitorum superficialis muscle of alcoholics with neurological signs showed a marked decrease and delayed recovery of pH, but rapid recovery of PCr index indicating that the muscle produces lactate during and after exercise to maintain the ATP level. To clarify the reason for this preference for anaerobic metabolism, we conducted simultaneous measurements of the muscle blood supply during and after exercise by using the near-infrared light method and energy metabolism by using 31P-magnetic resonance spectroscopy. In alcoholics with neurological signs, we observed a significant increase of oxyhemoglobin after exercise with a slight increase of total hemoglobin. In healthy volunteers and chronic alcoholics without neurological signs, such an overshoot of oxyhemoglobin was not observed. We conclude that chronic alcoholics with neurological signs have an abnormality of aerobic metabolism owing to muscle mitochondrial dysfunction.

Acid-Base Equilibrium↗
PubMed1989

Metabolic changes and mitochondrial dysfunction early following transthoracic countershock in dogs.

The mechanisms of myocardial injury and necrosis following transthoracic shocks from a direct current cardiac defibrillator were investigated in adult greyhounds. Myocardial lactate extraction became negative maximally at 1 minute, following two (mean -22% +/- SEM23) or five (-193% +/- 135) shocks and returned to baseline in 6-15 minutes. Myocardial necrosis assessed at 4 hours following the shock period was 0.05 g (+/- 0.03) after two shocks, 6.69 g (+/- 1.76) after five shocks and zero in controls. In further experiments, dogs received five or zero (dummy) shocks and mitochondria were isolated from their hearts following excision within 1 minute of receiving the final shock. Maximal oxygen consumption in right ventricular mitochondria was lower than the unshocked controls with both glutamate (66.9 +/- 9.4 nanoatoms of oxygen/mg per minute, n = 9 vs 86.6 +/- 13.6 nanoatoms/mg per minute, n = 7) and succinate (96.2 +/- 8.7 nanoatoms/mg per minute, n = 9 vs 119.5 +/- 14.4 nanoatoms/mg per minute, n = 7) as substrates. Using electron spin resonance spectroscopy, an increase in a peroxyl-free radical with g = 2.031 was detected in myocardial tissue after two internal shocks (50 joules stored energy, 0.5-minute intervals). We conclude that mitochondrial dysfunction and free-radical generation are likely contributors to cellular injury following multiple countershocks.

Animals↗
PubMed2002

Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment.

Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and gamma-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Lung mitochondrial dysfunction in pulmonary hypertension syndrome. I. Site-specific defects in the electron transport chain.

The main objectives of this study were to determine a) site-specific defects in the electron transport chain of lung mitochondria of broilers with pulmonary hypertension syndrome (PHS), b) if these defects are attenuated by high dietary vitamin E, and c) if these defects have a genetic basis. In Experiment 1, lung mitochondria were isolated from broilers with and without PHS fed diets containing 15 IU and 100 IU dl-alpha-tocopherol acetate/kg (VE); the four treatments were control, VE, PHS, and VE-PHS, respectively. Hydrogen peroxide (H2O2) generation in isolated lung mitochondria was monitored by dichlorofluorosein (DCF) fluorescence in response to chemicals that inhibit electron flow at specific sites on the electron transport chain using a 96-well microplate with Cytoflour (excitation/emission 480/530 nm). Basal H2O2 production was higher in PHS than in control mitochondria. Differences in H2O2 production between control and PHS were magnified by inhibition of Complexes I and III (Coenzyme Q) of the respiratory chain in mitochondria. Functional defects in PHS mitochondria were attenuated by high dietary VE. In Experiment 2, basal H2O2 production and that following inhibition of Complexes I and III were lower in lung mitochondria isolated from broilers selected for genetic resistance to PHS than in nonselected birds in the base population. The results of this study indicate that site-specific defects in Complexes I and III may underlie lung mitochondrial dysfunction in broilers with PHS, that these defects are attenuated by high dietary vitamin E, and that these defects may be related to genetic predisposition to PHS.

Animals↗