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PubMed2006

Conditional knockout of Mn superoxide dismutase in postnatal motor neurons reveals resistance to mitochondrial generated superoxide radicals.

Mitochondrial dysfunction and oxidative damage are implicated in the pathogenesis of neurodegenerative disease. Mice deficient in the mitochondrial form of superoxide dismutase (SOD2) die during embryonic or early postnatal development, precluding analysis of a pathological role for superoxide in adult tissue. Here, we generated postnatal motor neuron-specific SOD2 knockouts by crossing mice with floxed SOD2 alleles to VAChT-Cre transgenic mice in which Cre expression is restricted to postnatal somatomotor neurons. SOD2 immunoreactivity was specifically lost in a subset of somatomotor neurons resulting in enhanced superoxide production. Yet extensive histological examination revealed no signs of oxidative damage in animals up to 1 year after birth. However, disorganization of distal nerve axons following injury was accelerated in SOD2-deficient motor neurons. These data demonstrate that postnatal motor neurons are surprisingly resistant to oxidative damage from mitochondrial-derived superoxide radicals, but that such damage may sensitize axons to disorganization following nerve injury.

Animals↗
PubMedDate not supplied

Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease.

Evidence suggests that mitochondrial dysfunction is prominent in Alzheimer's disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.

Adenosine Triphosphate↗
PubMed1997

Rett syndrome: neurobiological changes underlying specific symptoms.

Rett syndrome (RS) is a progressive disorder that is predominant in females. It is associated with cortical atrophy, stereotyped hand movements mimicking hand-washing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The cause of RS is unknown; no consistent genetic abnormalities, at either the cellular or mitochondrial levels, have been identified. The diagnosis still depends solely upon clinical evidence. The clinical progression of RS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of appropriate trophic factors. Neuropathological studies have confirmed (1) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Biochemical studies have identified (1) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of beta-endorphin levels in the thalamus and glutamate levels in the CSF; (4) no evidence for mitochondrial dysfunction. These data suggest that there is a primary deficit in cholinergic function that might underlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RS is a neurodevelopmental disorder that has its greatest effects upon a limited number of neural systems during the first few years of postnatal life.

Humans↗
PubMed1994

Mechanism of cytotoxicity of paraquat. III. The effects of acute paraquat exposure on the electron transport system in rat mitochondria.

The effects of acute paraquat exposure on mitochondrial function in rat lung were studied. The paraquat dose-response study and time-effective study were performed to prove our hypothesis, enzyme toxicity especially in electron transport system following lipid peroxidation of mitochondrial inner membrane. In dose-response study, lipid peroxidation was increased by high dose paraquat exposure (40 mg/kg body weight) in rat lung, but not by low dose exposure (10 mg/kg body weight). But paraquat inhibited NADH:ubiquinone oxidoreductase (complex I) activities, especially NADH:ubiquinone reaction (NQR), even in low dose exposure. The lipid peroxide concentration did not correspond to the damage of complex I activity. In paraquat time-effective study, both lung and blood lipid peroxides increased after 6 h of paraquat exposure, decreased after 12 and 24 h and increased again after 48 h. After first peak of lipid peroxidation, NQR velocity decreased earlier than NADH:ferricyanide reaction (NFR) velocity. From these results, the cytotoxicity via mitochondrial dysfunction by acute paraquat exposure might be caused by complex I toxicity following lipid peroxidation of mitochondrial inner membrane.

Animals↗
PubMedDate not supplied

Selective depletion of mitochondrial glutathione concentrations by (R,S)-3-hydroxy-4-pentenoate potentiates oxidative cell death.

The hepatocellular glutathione content is partitioned into a cytosolic pool, which accounts for about 85% of the cellular glutathione content, and a mitochondrial pool, which accounts for about 15% of the cellular glutathione content. Previous studies indicated that the mitochondrial glutathione pool may play a critical role in cytoprotection against xenobiotic-induced cell damage. Tests of the role of mitochondrial glutathione in cytoprotection have been hampered by the lack of agents that selectively deplete the mitochondrial glutathione pool. To test the hypothesis that mitochondrial glutathione plays a critical role in protecting against cytotoxic agents, we developed a method to deplete selectively mitochondrial glutathione concentrations. (R,S)-3-Hydroxy-4-pentenoate, an analog of (R)-3-hydroxybutanoate, caused a rapid and selective depletion of mitochondrial glutathione concentrations. Incubation of (R,S)-3-hydroxy-4-pentenoate with rat liver mitochondria or with 3-hydroxybutyrate dehydrogenase in the presence of glutathione afforded a glutathione conjugate whose chromatographic properties were identical with synthetic S-(3-oxo-4-carboxybutyl)glutathione, indicating that (R,S)-3-hydroxy-4-pentenoate was oxidized to the Michael acceptor 3-oxo-4-pentenoate, which reacts with glutathione. Exposure of rat hepatocytes to (R,S)-3-hydroxy-4-pentenoate, which was not cytotoxic and did not induce mitochondrial dysfunction, potentiated the cytotoxicity of tert-butyl hydroperoxide. These results establish the critical role of mitochondrial glutathione in cytoprotection and demonstrate and (R,S)-3-hydroxy-4-pentenoate may find utility in exploring mitochondrial glutathione homeostasis.

Animals↗
PubMed2005

Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function.

Here, we investigated the role of telomerase on Bcl-2-dependent apoptosis. To this end, the 4625 Bcl-2/Bcl-xL bispecific antisense oligonucleotide and the HA14-1 Bcl-2 inhibitor were used. We found that apoptosis induced by 4625 oligonucleotide was associated with decreased Bcl-2 protein expression and telomerase activity, while HA14-1 triggered apoptosis without affecting both Bcl-2 and telomerase levels. Interestingly, HA14-1 treatment resulted in a profound change from predominantly nuclear to a predominantly cytoplasmic localization of hTERT. Downregulation of endogenous hTERT protein by RNA interference markedly increased apoptosis induced by both 4625 and HA14-1, while overexpression of wild-type hTERT blocked Bcl-2-dependent apoptosis in a p53-independent manner. Catalytically and biologically inactive hTERT mutants showed a similar behavior as the wild-type form, indicating that hTERT inhibited the 4625 and HA14-1-induced apoptosis regardless of telomerase activity and its ability to lengthening telomeres. Finally, hTERT overexpression abrogated 4625 and HA14-1-induced mitochondrial dysfunction and nuclear translocation of hTERT. In conclusion, our results demonstrate that hTERT is involved in mitochondrial apoptosis induced by targeted inhibition of Bcl-2.

Apoptosis↗
PubMed2005

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast.

Autophagy, a highly regulated programme found in almost all eukaryotes, is mainly viewed as a catabolic process that degrades nonessential cellular components into molecular building blocks, subsequently available for biosynthesis at a lesser expense than de novo synthesis. Autophagy is largely known to be regulated by nutritional conditions. Here we show that, in yeast cells grown under nonstarving conditions, autophagy can be induced by mitochondrial dysfunction. Electron micrographs and biochemical studies show that an autophagic activity can result from impairing the mitochondrial electrochemical transmembrane potential. Furthermore, mitochondrial damage-induced autophagy results in the preferential degradation of impaired mitochondria (mitophagy), before leading to cell death. Mitophagy appears to rely on classical macroautophagy machinery while being independent of cellular ATP collapse. These results suggest that in this case, autophagy can be envisioned either as a process of mitochondrial quality control, or as an ultimate cellular response triggered when cells are overwhelmed with damaged mitochondria.

Adenosine Triphosphate↗
PubMed1996

In vitro characterization of HIV type 1 biological clones from asymptomatic and symptomatic pediatric patients.

To investigate the mechanisms of HIV-1 cytopathogenicity, functional biological HIV-1 clones were isolated from two infected children with high viral loads in vivo. Clone HC4 was isolated from a symptomatic child and clone GC6 8-4 was isolated from an asymptomatic child. These clones were characterized for their ability to induce syncytia, and to replicate and induce single-cell death in peripheral blood-derived normal CD4 T cell cultures containing anti-CD4 antibody. Despite similar viral loads as determined by p24 antigen production or viral RNA expression, GC6 8-4 was noncytopathogenic and HC4 was cytopathogenic. Since we had demonstrated that mitochondrial dysfunction correlated with HIV-1-induced cell death, we determined whether the cytopathogenic HC4 clone decreased mitochondrial viability using a mitochondrial-specific dye, rhodamine-123. Following infection, mitochondrial viability decreased in cells infected with HC4 by day 4 and continued to decline through day 7 when compared to uninfected cells. By day 7 postinfection, greater than 80% of the cells in culture were dead. Similar analyses on CD4 T cells infected with the noncytopathogenic GC6 8-4 demonstrated that mitochondria remained functionally viable and > 90% of the cells excluded trypan blue. These studies describe a cell culture system to study single-cell death in the absence of syncytia and secondary infection. Results with two patient-derived HIV-1 biological clones suggest that loss of mitochondrial viability may play a role in HIV-1-induced cytopathogenicity.

CD4-Positive T-Lymphocytes↗
PubMed1993

Maternally transmitted partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus.

Mitochondrial DNA from a 38 year old male with diabetes mellitus and features of mitochondrial dysfunction was analysed and shown to include a population with a partial duplication. The partially duplicated mitochondrial DNA molecules were evident in both muscle and blood. The region of mitochondrial DNA duplicated includes the origin of heavy strand replication, but not the light strand origin. This patient has features in common with other cases of partial direct tandem duplications and with a family which was reported to harbour a 10.4 kb mtDNA deletion. Initial restriction enzyme analysis of our case produced results consistent with a partial deletion of mitochondrial DNA. This leads us to propose that the rarity of reports of partial mitochondrial DNA duplications may stem in part from the classification of such mutants as partial deletions.

Adult↗
PubMed2003

Marked aging-related decline in efficiency of oxidative phosphorylation in human skin fibroblasts.

An extensive analysis has been carried out of mitochondrial biochemical and bioenergetic properties of fibroblasts, mostly skin-derived, from a large group of subjects ranging in age between 20 wk fetal and 103 yr. A striking age-related change observed in a fundamental process underlying mitochondrial biogenesis and function was the very significant decrease in rate of mitochondrial protein synthesis in individuals above 40 yr. The analysis of endogenous respiration rate revealed a significant decrease in the age range from 40 to 90 yr and a tendency to uncoupling in the samples from subjects above 60 yr. A surprising finding was the occurrence of a subgroup of individuals >or=90 yr old whose skin fibroblasts exhibited an exceptionally high respiration rate. This high rate was not due to respiration uncoupling, rather pointing to a compensatory phenomenon, not involving an increase in mtDNA content, in the corresponding skin fibroblast populations, or, possibly, to a selection of a different cell type secondary to more extensive dermal atrophy. The most important aging-related phenotypic effects observed were those that affected the cell oxidative phosphorylation (OX-PHOS) capacity. These were, in particular, the very significant reduction in the ratio of uncoupled to oligomycin-inhibited endogenous respiration observed in intact fibroblasts, which pointed to a decrease with donor's age in the control of respiration by the mitochondrial membrane potential, the very significant decrease in efficiency of OX-PHOS, as determined by novel in situ measurements of P:O ratios, and, consistent with these results, the very significant reduction in the respiratory control ratios. These findings clearly pointed to a dramatic mitochondrial dysfunction, which would lead to a decrease in ATP synthesis rate, with the observed decline in mitochondrial protein synthesis rate being a likely contributing factor. These observations have important implications for understanding the biology of aging, as well as the pathogenesis of aging-related degenerative diseases.

Adolescent↗
PubMed2006

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Adolescent↗
PubMed1998

Enhanced fatigue during motor performance in patients with Parkinson's disease.

OBJECTIVE: To measure fatigue quantitatively during continuous motor performance in patients with PD. BACKGROUND: Enhanced fatigue on performance of motor tasks is a very frequent and disabling complaint of PD patients, and is poorly characterized and understood. Recent evidence suggests a role for mitochondrial dysfunction in the pathogenesis of PD. Reduced exercise capacity is one of the hallmarks of systemic mitochondrial impairment. METHODS: The authors used an automated system to measure muscle fatigue during a continuous (30-second), maximal, isometric forearm flexion in 17 PD patients and 10 age-matched control subjects. A fatigue index (FI) was then calculated. Peak force (PF) was measured as an internal standard of the examination. Measurements were performed before and 2 hours after an oral dose of levodopa/carbidopa (125 mg/12.5 mg). RESULTS: In PD patients there was a 50% increase in FI. The increased FI was often asymmetric and more pronounced on the side more affected by the disease. FI was significantly responsive to, and improved after, an oral dose of levodopa. The rate of improvement in FI induced by levodopa correlated with disease severity, as measured by the Unified Parkinson's Disease Rating Scale. No significant alterations in PF were observed. CONCLUSIONS: Enhanced muscle fatigue should be recognized as an integral part of the spectrum of motor impairment of PD. However, our data argue for its association with a central dopamine deficiency rather than with a muscle mitochondrial abnormality.

Adult↗
PubMed1995

Developmental changes in newborn lamb brain mitochondrial activity and postasphyxial lipid peroxidation.

Previously, our laboratory has demonstrated inhibition of mitochondrial state 3 (ADP-dependent) respiration 5 min after resuscitation from an asphyxial insult in lambs less than 3 days of age. Older lambs were resistant to this transient mitochondrial dysfunction. This study was designed to examine if age-related differences in baseline state 3 mitochondrial respiration, electron transport chain activity, or susceptibility to oxygen free radical-mediated lipid peroxidation were related to the previously observed differences in postasphyxial mitochondrial respiration. Mitochondrial respiration was measured in 24 nonasphyxiated control lambs aged 1-10 days using four different substrates. Electron transport chain activity was assessed in 15 of these lambs, and lipid peroxidation measured as conjugated diene production was measured in 11 of these lambs. These lambs were all ventilated to maintain normal blood gases for a time period equal to the length of the hypoxic insult in asphyxiated lambs (see below), after which samples of brain were removed for isolation of mitochondria. A second group of 11 lambs (seven < or = 3 days of age and four > 3 days of age) were asphyxiated. The insult was a 75-to-90-min episode of hypoxia and hypercarbia that resulted in bradycardia and systemic hypotension over the final 15 min of the insult. At the end of asphyxia, the lambs were resuscitated and returned to control ventilator settings. Samples of brain were removed 5 min after resuscitation. Postasphyxia electron transport chain activity and lipid peroxidation were measured. All measurements described above were done in both nonsynaptic (primarily glial in origin) and synaptic mitochondria. State 3 mitochondrial respiration varied significantly with age, decreasing by an average of 41.2% +/- 11.1% (mean +/- SEM) from Day 2 to Day 5-6 and then increasing back to levels similar to Day 2 by Day 8-10 in nonsynaptic mitochondria. State 3 respiration in synaptic mitochondria decreased 60.6% +/- 5.2% from Day 2 to Day 5-6 before returning to levels similar to Day 2 by Day 8-10. Resting (nonADP-dependent) state 4 respiration demonstrated similar developmental patterns. Electron transport chain activities did not vary with age in the nonasphyxiated control animals. In addition, an asphyxial insult did not diminish electron transport chain activities in either lambs < or = 3 days old or those > 3 days of age.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine Nucleotides↗
PubMedDate not supplied

Biochemical and antiarrhythmic effects of three calcium channel antagonists in ischemic canine hearts.

The cardioprotective and antiarrhythmic effects of diltiazem, nilvadipine, and verapamil were evaluated in 33 dogs. The left anterior descending coronary artery (LAD) was occluded for two hours, 25 minutes after saline administration (controls); ten minutes after diltiazem (0.25 mg/kg); 15 minutes after nilvadipine (1 micrograms/kg/min); or ten minutes after verapamil (0.4 mg/kg). Changes in blood pressure and heart rate were monitored throughout the experiment. Two hours after LAD occlusion, mitochondria were prepared from ischemic and nonischemic areas and their function was measured polarographically. Fractionation of myocardial tissue from the ischemic and nonischemic areas was performed and activities of lysosomal enzymes were measured. LAD occlusion induced mitochondrial dysfunction and leakage of lysosomal enzymes in the ischemic area. Administration of the calcium antagonists preserved mitochondrial function and prevented leakage of lysosomal enzymes. All three calcium antagonists reduced the incidence of ventricular arrhythmias during ischemia. The results indicate that calcium may play an important role in the development of biochemical and electrical disturbances during ischemia.

Acetylglucosaminidase↗
PubMed1990

Heteroplasmy in chronic external ophthalmoplegia: clinical and molecular observations.

Chronic progressive external ophthalmoplegia (CPEO) describes a recognizable clinical syndrome frequently associated with variable dysfunction in other organ systems. Histochemical and biochemical studies suggested primary dysfunction of oxidative phosphorylation. This has recently been confirmed by demonstration of partially deleted as well as normal mitochondrial DNA--heteroplasmy--in some of these patients, most of them sporadic. In the six heteroplasmic CPEO patients that we have examined to date, the partially deleted species has been detected in all tissues tested, albeit in vastly different proportions. We report here detection of physiologically significant proportions of partially deleted mitochondrial DNA in several organs taken at autopsy from a CPEO patient with severe multisystem disease. We discuss the relationship of CPEO to several other clinical phenotypes associated with mitochondrial dysfunction, and discuss the possible implications of heteroplasmy for the development of variable phenotypes.

Child↗
PubMed2002

Platelet-activating factor induces permeability transition and cytochrome c release in isolated brain mitochondria.

Platelet-activating factor (PAF), a potent bioactive phospholipid implicated in neuronal excitotoxic death, was assessed as a mediator of brain mitochondrial dysfunction. Carbamyl PAF, a non-hydrolyzable PAF analog, added to neurons in culture resulted in decreased mitochondrial membrane potential (DeltaPsi(M)) as measured by the DeltaPsi(M)-sensitive fluorophore 5,5', 6,6'-tetrachloro-1, 1', 3,3'-tetraethylethylbenzimidazolo-carbocyanide iodide (JC-1). To investigate whether PAF has a direct effect on the mitochondria, the mediator was added to rat brain mitochondria preparations and an increase in the permeability of the mitochondrial membrane, termed permeability transition (PT), and cytochrome c release were measured. We report that PAF causes both dose-dependent PT and cytochrome c release from isolated mitochondria. Furthermore, the selective PAF antagonist tetrahydro-4,7,8,10 methyl-1 (chloro-2 phenyl)-6 (methoxy-4 phenyl-carbamoyl)-9 pyrido [4',3'-4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4 (BN50730), which has affinity for intracellular binding sites, and the peripheral benzodiazepine receptor ligands 7-chloro-5- [4'-chlorophenyl]-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864) and 1-(-2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), inhibit PAF induction of PT and cytochrome c release. These results suggest that PAF excitotoxicity involves, at least in part, alterations of the mitochondrial membrane.

Animals↗
PubMed2005

Mitochondrial DNA 3243A>G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia.

BACKGROUND: Accumulating evidence suggests mitochondrial dysfunction in bipolar disorder. Analyses of mitochondria-related genes using DNA microarray showed significantly increased LARS2 (mitochondrial leucyl-tRNA synthetase) in the postmortem prefrontal cortices of patients with bipolar disorder provided by the Stanley Foundation Brain Collection. LARS2 is a nuclear gene encoding the enzyme catalyzing the aminoacylation of mitochondrial tRNA(Leu). A well-studied mitochondrial DNA point mutation, 3243A>G, in the region of tRNA(Leu (UUR)), related with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), is known to decrease the efficiency of aminoacylation of tRNA(Leu (UUR)). METHODS: The steady state level of LARS2 was examined in the transmitochondrial cybrids carrying 3243A>G. We examined the 3243A>G mutation in these brains using the peptide nucleic acid-clamped polymerase chain reaction restriction fragment length polymorphism method. RESULTS: LARS2 was upregulated in the transmitochrondrial cybrids carrying 3243A>G. The 3243A>G was detected in the postmortem brains of two patients with bipolar disorder and one with schizophrenia. These patients also showed higher levels of the mutation in their livers and significantly higher gene expression of LARS2 compared with other subjects. CONCLUSIONS: These results suggest that upregulation of LARS2 is a hallmark of 324A>G mutation. The accumulation of 3243A>G mutation in the brain may have a pathophysiologic role in bipolar disorder and schizophrenia.

Adult↗
PubMed2004

Oligomycin and antimycin A prevent nitric oxide-induced apoptosis by blocking cytochrome C leakage.

Nitric oxide (NO) is a potent inducer of apoptosis, and its cytotoxicity is closely related to mitochondrial dysfunction. In this study we investigated the effects of a F0F1-ATPase inhibitor, oligomycin, and a mitochondrial respiratory chain complex III inhibitor, antimycin A, on NO-induced apoptosis. We used a normal rat gastric-epithelium cell line, RGM-1, treated with a pure NO donor, NOC-1 -1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene - in the presence or absence of oligomycin or antimycin A. Changes in the expressions of Bax or Bcl-2 proteins, release of cytochrome C from mitochondria into the cytosol, activation of caspase-3, and changes in the mitochondrial membrane potential (DeltaPsi) were measured with the use of Western blotting, c43 lorimetric assays, and a mitochondrial potential sensor, JC-1 dye. Treatment with NOC-18 induced dose-dependent apoptotic cell death in RGM-1 cells. Cell death was accompanied by mitochondrial depolarization, increases in Bax protein expression and cytochrome C leakage, and, subsequently, caspase-3 activation. Oligomycin and antimycin A prevented NO-induced apoptosis in a dose-dependent fashion by preventing cytochrome C release independent of Bcl-2 expression. However, neither compound affected the up-regulation of Bax protein. On the one hand, oligomycin treatment was not accompanied by a decline in DeltaPsi. On the other hand, antimycin A treatment decreased DeltaPsi regardless of NOC-18 treatment. The findings of this study suggest that various functional molecules that constitute the mitochondrial respiratory chain may contribute to cytochrome C release that occurs during NO-induced apoptosis.

Adenosine Triphosphate↗