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PubMed2001

[The role of mitochondrial respiratory chain in the pathogenesis of ALS].

Mitochondrial dysfunction and abnormal electron chain transport (ECT) may be involved in the pathogenesis of ALS. The aim of this study was to investigate the effect of cerebrospinal fluid (CSF) from ALS patients on the activity of ECT enzymes in mitochondrial cerebral crude preparations in the rats. We found that CSF inhibited the activity of complex I-III in 20%, complex II-III in 12% and complex IV in 33% of the ALS patients. CSF from the controls did not affect the activity of complex I-III and II-III. The effect of the CSF ultrafiltrates with cut off below 5000 daltons on the activity of ECT enzymes was also investigated. The CSF ultrafiltrates inhibited the activity of complex I-III, complex II-III and complex IV in 38%, 44% and 53% of the ALS patients, and in 80%, 53% and 43% of the controls, respectively. The results of this study and our previously reported experiments on the sera of ALS patients may indicate that neurotoxic effects of body fluids from ALS patients could be mediated by inhibition of the respiratory chain enzymes. This confirms an important role of mitochondrial dysfunction in the pathogenesis of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression.

OBJECTIVES: Activity of mitochondrial respiratory chain complexes with and without mitochondrially encoded subunits was assessed in failing human myocardium together with parameters of mitochondrial gene expression. BACKGROUND: Mutations and deletions in mitochondrial genome (mtDNA) sporadically accumulate in the aging myocardium. In experimental heart failure, they are discussed to be a generalized problem resulting in disturbances of mitochondrial gene expression and mitochondrial function. METHODS: In left ventricular specimens from 43 explanted failing hearts and 10 donor hearts, enzyme activities of respiratory chain complexes, messenger ribonucleic acid (mRNA) expression of mitochondrially and nuclear encoded mitochondrial components (reverse transcriptase-polymerase chain reaction, Northern blot), undeleted wildtype mtDNA (Southern blot), and nuclear encoded mitochondrial transcription factor A (mtTFA) (Western blot) were quantified. RESULTS: Citrate synthase normalized activity of mitochondrial respiratory chain complex I, which contains seven mitochondrially encoded subunits, was decreased by 28% in terminally failing myocardium, whereas the activity of the exclusively nuclear encoded complex II was unchanged. However, the amount of intact mtDNA, the mRNA of all mitochondrially encoded subunits of the entire respiratory chain, the amount of mtTFA, and the enzymatic activity of complex III and complex IV, which also contain mitochondrially encoded subunits, were normal compared with donor hearts, excluding generalized disturbance of mitochondrial gene expression. Retrospective analysis of drug therapy before transplantation identified beta-blockers as one putative protection against this disturbance. CONCLUSIONS: In terminally failing human myocardium of patients receiving drug therapy, complex I depression is not caused by mtDNA damage and disturbed mitochondrial gene expression. The absence of mtDNA damage should facilitate recovery of the overloaded myocardium, if effective unloading could be achieved.

Adrenergic beta-Antagonists↗
PubMed2006

Expression of chaperonin 60 in the hippocampus of the streptozotocin diabetic rat.

Mitochondrial dysfunction and oxidative stress are implicated in the pathological changes observed in the diabetic central nervous system. In this study, using the streptozotocin-induced diabetic rat model we document for the first time the over-expression of a mitochondrial specific stress protein (chaperonin 60) in the CA1/CA3 regions of the diabetic hippocampus in the absence of neurodegeneration. The increase in expression of chaperonin 60 was not observed in the cohort treated with insulin, suggesting that the observed effect was not due to streptozotocin per se but due to the hyperglycaemic state induced by the diabetic state. The expression of chaperonin 60 was also positively correlated with a marker of mitochondrial oxidative stress (manganese superoxide dismutase). We suggest that chaperonin 60 could be an early event marker of mitochondrial dysfunction in the diabetic central nervous system and indeed be neuroprotective in the early stages of hyperglycaemic-induced oxidative stress.

Animals↗
PubMed2004

Caspase-independent component of retinal ganglion cell death, in vitro.

PURPOSE: Although in vitro and in vivo models demonstrate caspase activation in retinal ganglion cells (RGCs) undergoing apoptosis, the caspase-independent component of RGC death is unclear. Identification of the precise mechanisms of cell death in these distinct neurons is essential for the development of effective neuroprotective strategies in glaucoma. Because TNF-alpha and hypoxia have been implicated in RGC death during glaucomatous optic nerve degeneration, this study was conducted to determine whether RGCs survive exposure to TNF-alpha or hypoxia in the presence of caspase inhibitor treatment, and whether mitochondrial dysfunction is involved in RGC death induced by these glaucomatous stimuli. METHODS: Primary cultures of rat RGCs were exposed to TNF-alpha or hypoxia for up to 48 hours. The temporal relationship of RGC death with the loss of mitochondrial membrane potential and the release of cell death mediators, including cytochrome c and apoptosis-inducing factor (AIF), was studied in the absence and presence of specific inhibitors of caspases. In addition, treatment with a free-radical scavenger, 4-hydroxytetramethylpiperidine-1-oxyl (tempol; 5 mM), was used in some experiments. Cell viability was assessed using calcein assay, and annexin V binding combined with propidium iodide staining was used for the distinction of apoptotic and necrotic cells. Caspase-3-like protease activity was measured using a fluorometric assay, and for the in situ detection of caspase activity, immunocytochemistry was performed with a cleavage-site-specific antibody. The time course of alterations in the mitochondrial membrane potential and the release of cell death mediators in individual cells undergoing cell death were assessed with a fluorescent tracer and subsequent immunocytochemistry. In addition, a fluorescent dye, dihydroethidium was used to assess the generation of reactive oxygen species (ROS). RESULTS: Findings of this study revealed that the loss of mitochondrial membrane potential and the release of cell death mediators accompanied RGC death induced by TNF-alpha or hypoxia. Although caspase inhibitor treatment temporarily decreased the rate of apoptosis, caspase inhibition was not adequate to block RGC death if the mitochondrial membrane potential was lost and mitochondrial mediators were released. Despite the inhibited caspase activity, survival rate was less than 70% after a 48-hour incubation with death stimuli, and both apoptotic and necrotic cells were detectable in these cultures. When combined with caspase inhibition, tempol reduced the production of ROS and provided an additional 20% increase in RGC survival. CONCLUSIONS: Based on these novel findings, RGC death induced by TNF-alpha or hypoxia involves a caspase-independent component, and reducing the free-radical generation provides additional protection of RGCs temporarily saved by caspase inhibition. Therefore, neuroprotective strategies in glaucoma should include tools to improve the ability of these neurons to survive the cytotoxic consequences of mitochondrial dysfunction.

Animals↗
PubMed1996

Changes in labile energy metabolites, redox state and intracellular pH in postischemic brain of normo- and hyperglycemic rats.

The present experiments were undertaken to study how preischemic hyperglycemia, which is known to exaggerate ischemic damage and to trigger delayed postischemic seizures affects the bioenergetic state and the intracellular pH (pHi) of brain tissue at early (6 h) and late (18 h) recirculation times. To that end, normo- and hyperglycemic rats were subjected to 10 min of forebrain ischemia, and neocortical tissue was frozen in situ for analyses of labile energy metabolites. Animals with preischemic hyperglycemia failed to show a postischemic reduction of the phosphorylation state of the adenine nucleotide pool, or a rise in tissue lactate content, nor did they show a change in tissue redox state. However, the hyperglycemia led to a rise in phosphocreatine (PCr) content after 6 h of recirculation. Calculations of intracellular pH (pHi) from the creatine kinase (CK) equilibrium showed a rise in pHi above normal, a finding which was supported by a limited number of 5,5-dimethyl[2-14C]oxazolidine-2,4-dione (DMO) measurements. The preischemic hyperglycemia also blunted the postischemic rise in tissue glycogen content, which is usually observed in normoglycemic rats. The results thus fail to reveal that the hyperglycemia-triggered, massive exaggeration of ischemic brain damage, which is heralded by generalized seizures after 18-24 h of recirculation, is preceded by mitochondrial dysfunction of a degree which affects the bioenergetic state or the redox potential of the tissue. However, the results suggest that the hyperglycemia enhances and/or prolongs the postischemic alkalosis. It is discussed whether the rise in pH contributes to the mitochondrial dysfunction which subsequently develops.

Analysis of Variance↗
PubMed2006

Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III.

Mitochondrial dysfunction may play an important role in the pathogenic mechanism of Huntington's disease (HD). However, the exact mechanism by which mutated huntingtin could cause bioenergetic dysfunction is still unknown. We have constructed a stable inducible yeast model of HD by expressing a human huntingtin fragment containing a mutant polyglutamine tract of 103Q fused to green fluorescent protein (GFP), and a control expressing a wild-type 25Q domain fused to GFP in a wild-type strain. We showed that in yeast cells expressing 103Q, cell respiration was progressively reduced after 4-6 h of induction with galactose, down to 50% of the control after 10 h of induction. The cell respiration defect results from an alteration in the function and amount of mitochondrial respiratory chain complex II+III, in congruency to data obtained from postmortem brain of HD patients and from toxin models. In our model, the production of reactive oxygen species (ROS) is significantly enhanced in cells expressing 103Q. Quenching of ROS with resveratrol partially prevents the cell respiration defect. Mitochondrial morphology and distribution were also altered in cells expressing 103Q, probably resulting from the interaction of aggregates with portions of the mitochondrial web and from a progressive disruption of the actin cytoskeleton. We propose a mechanism for mitochondrial dysfunction in our yeast model of HD in which the interactions of misfolded/aggregated polyglutamine domains with the mitochondrial and actin networks lead to disturbances in mitochondrial distribution and function and to increase in ROS production. Oxidative damage could preferentially affect the stability and function of enzymes containing iron-sulfur clusters such as complexes II and III. Our yeast model represents a very useful paradigm to study mitochondrial physiology alterations in the pathogenic mechanism of HD.

Green Fluorescent Proteins↗
PubMed1999

Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential.

Cardiac myocyte apoptosis is potentially important in many cardiac disorders. In other cells, Bcl-2 family proteins and mitochondrial dysfunction are probably key regulators of the apoptotic response. In the present study, we characterized the regulation of antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax) Bcl-2 family proteins in the rat heart during development and in oxidative stress-induced apoptosis. Bcl-2 and Bcl-xL were expressed at high levels in the neonate, and their expression was sustained during development. In contrast, although Bad and Bax were present at high levels in neonatal hearts, they were barely detectable in adult hearts. We confirmed that H(2)O(2) induced cardiac myocyte cell death, stimulating poly(ADP-ribose) polymerase proteolysis (from 2 hours), caspase-3 proteolysis (from 2 hours), and DNA fragmentation (from 8 hours). In unstimulated neonatal cardiac myocytes, Bcl-2 and Bcl-xL were associated with the mitochondria, but Bad and Bax were predominantly present in a crude cytosolic fraction. Exposure of myocytes to H(2)O(2) stimulated rapid translocation of Bad (<5 minutes) to the mitochondria. This was followed by the subsequent degradation of Bad and Bcl-2 (from approximately 30 minutes). The levels of the mitochondrial membrane marker cytochrome oxidase remained unchanged. H(2)O(2) also induced translocation of cytochrome c from the mitochondria to the cytosol within 15 to 30 minutes, which was indicative of mitochondrial dysfunction. Myocytes exposed to H(2)O(2) showed an early loss of mitochondrial membrane potential (assessed by fluorescence-activated cell sorter analysis) from 15 to 30 minutes, which was partially restored by approximately 1 hour. However, a subsequent irreversible loss of mitochondrial membrane potential occurred that correlated with cell death. These data suggest that the regulation of Bcl-2 and mitochondrial function are important factors in oxidative stress-induced cardiac myocyte apoptosis.

Aging↗
PubMed2000

Increased apoptosis in acquired sideroblastic anaemia.

Idiopathic acquired sideroblastic anaemias (IASAs) form a subgroup of the myelodysplastic syndromes and are characterized by mitochondrial iron accumulation, bone marrow erythroid hyperplasia and decreased peripheral red blood cell counts. Increased intramedullary apoptosis of erythroid precursors is presumed to constitute the pathophysiological mechanism explaining this ineffective erythropoiesis, but if and how mitochondrial dysfunction is implicated in this process is currently unknown. We therefore studied bone marrow precursor cells obtained from nine patients with IASA for (i) caspase 3 activity, (ii) numbers of Annexin V- and 7-amino-actinomycin-positive cells, (iii) numbers of cells with diminished mitochondrial membrane potential, Delta Psi(m), and (iv) numbers of cells producing reactive oxygen species (ROS), and we compared the results with those of five normal bone marrow samples. Compared with controls, we found increased caspase 3 activity in all IASA samples, which correlated with increased numbers of Annexin-V-positive cells (r = 0.7). Analysis of different subpopulations showed increased apoptosis in erythroid populations compared with myeloid and/or lymphoid populations in five out of nine cases, and increased apoptosis in the last two populations in four out of nine cases. As evidence of mitochondrial dysfunction, Delta Psi(m) was found to be diminished in the erythroid subpopulations of all cases of IASA (66.6 +/- 17% vs. 34.6 +/- 12% in normals). Delta Psi(m) decrease was correlated to Annexin V positivity (r = 0.7). Astonishingly, no difference was found between IASA and normal bone marrows with regard to the number of ROS-producing cells. In fact, both groups exhibited a similar low proportion of ROS production (10.3 +/- 7% in normals vs. 6.8 +/- 5% in IASA). Taken together, our results show that mitochondria are clearly implicated in the apoptotic process in IASA patients. Whether this is a result of an intramitochondrial defect (e.g. Fe accumulation, secondary to mitochondrial or nuclear DNA mutations) or is secondary to an extracellular stimulus [e.g. tumour necrosis factor (TNF), Fas ligand (FasL)] remains to be determined.

Adult↗
PubMed1994

Dysfunction of mouse liver mitochondria induced by 2,2'-azobis-(2-amidinopropane) dihydrochloride, a radical initiator, in vitro and in vivo.

Mouse liver mitochondria were uncoupled in a time dependent by intraperitoneal injection of a radical initiator, 2,2'-azobis-(2-amidinopropane) dihydrochloride (AAPH) (100 mg/kg). State 3 respiration, ADP/O ratio and respiratory control ratio (RCR) were decreased 30 min after injection but there was no effect on state 4 respiration. Lipid peroxidation was increased and oxidative phosphorylation was uncoupled at one hr after drug injection but gradually recovered to normal levels after 14 hr in vivo. State 3 respiration, RCR and ADP/O ratio but not state 4 respiration of isolated mouse mitochondria were inhibited by short term incubation with AAPH in vitro. This inhibitory action was concentration dependent (ID50 = 5 mM) but was not prevented by alpha-tocopherol. AAPH had no effect on electron transport or the membrane potential of these isolated mitochondria. However, mitochondria were uncoupled via lipid peroxidation and swelling by long term incubation with AAPH. These inhibitory effects of AAPH were reduced by its spontaneous degradation not only in vitro but also in vivo. Thus AAPH induces mitochondrial dysfunction by direct action in the early period of treatment and free radicals produced from AAPH mediate mitochondrial swelling via lipid peroxidation in the late period. From these findings, it is concluded that mitochondrial phosphorylation plays an important role in the pathogenesis of liver injury induced by AAPH and that radicals generated by AAPH might be a source of liver injury and mitochondrial dysfunction in vivo.

Amidines↗
PubMed2006

p53 mediates particulate matter-induced alveolar epithelial cell mitochondria-regulated apoptosis.

RATIONALE: Exposure to particulate matter (PM) causes lung cancer by mechanisms that are unknown, but p53 dysfunction is implicated. OBJECTIVE: We determined whether p53 is required for PM-induced apoptosis in both human and rodent alveolar type (AT) 2 cells. METHODS: A well-characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [DeltaPsi m] and caspase-9 activation), p53 protein and mRNA expression, and apoptosis (DNA fragmentation and annexin V staining) in vitro using A549 cells and primary isolated human and rat AT2 cells. The role of p53 was assessed using inhibitors of p53-dependent transcription, pifithrin-alpha, and a genetic approach (overexpressing E6 or dominant negative p53). In mice, the in vivo effects of PM causing p53 expression and apoptosis were assessed 72 h after a single PM intratracheal instillation. MEASUREMENTS AND MAIN RESULTS: PM-induced apoptosis in A549 cells was characterized by increased p53 mRNA and protein expression, mitochondrial translocation of Bax and p53, a reduction in DeltaPsi m, and caspase-9 activation, and these effects were blocked by inhibiting p53-dependent transcription. Similar findings were noted in primary isolated human and rat AT2 cells. A549-rho degrees cells that are incapable of mitochondrial reactive oxygen species production were protected against PM-induced DeltaPsi m, p53 expression, and apoptosis. In mice, PM induced p53 expression and apoptosis at the bronchoalveolar duct junctions. CONCLUSIONS: These data suggest a novel interaction between p53 and the mitochondria in mediating PM-induced apoptosis that is relevant to the pathogenesis of lung cancer from air pollution.

Animals↗
PubMed1999

The Tup1-Cyc8 protein complex can shift from a transcriptional co-repressor to a transcriptional co-activator.

Cyc8(Ssn6)-Tup1, a general co-repressor complex, is recruited to promoter DNA via interactions with DNA-binding regulatory proteins and inhibits the transcription of many different yeast genes. Previous studies have established that repression function of the complex is performed by one subunit of the complex, the Tup1 protein, and requires specific components of the RNA polymerase II holoenzyme such as Sin4 and Rgr1. In this study we test the transcriptional activity of the Cyc8 subunit using a lexA operator-containing reporter. We show that a LexA-Cyc8 hybrid stimulates transcription when expressed in a tup1Delta, a sin4Delta, or a rgr1Delta strain, suggesting that transcriptional activation is an intrinsic property of the Cyc8-Tup1 co-repressor. In support of this notion we demonstrate that Cyc8-Tup1 has a dual function on CIT2, a gene encoding a citrate synthase that is expressed upon mitochondrial dysfunction. First, we show that Cyc8-Tup1 is tethered to CIT2 promoter by interacting with the activation domain of Rtg3, a bHLH/L-Zip DNA-binding transactivator of CIT2. Next we demonstrate that Cyc8-Tup1 activates CIT2 transcription in response to mitochondrial dysfunction, and this stimulatory effect is mediated by Cyc8. In contrast, basal (noninduced) expression of this gene is inhibited by Tup1. These findings establish a positive role for the Cyc8-Tup1 complex in transcription and support a model by which specific metabolic signals may convert the Cyc8-Tup1 transcriptional co-repressor to a co-activator of certain promoters.

DNA-Binding Proteins↗
PubMed2006

Normal serum alanine concentration differentiates transient neonatal lactic acidemia from an inborn error of energy metabolism.

BACKGROUND: Elevated blood lactate levels are common in the critically ill neonate; however, sometimes they are difficult to interpret. Persistent or recurrent lactic acidemia might point to an inborn error of metabolism, like disturbances of the oxidative phosphorylation. Chronic lactic acidemia results in increased serum alanine levels. Serum alanine levels in newborns with transient lactic acidemia have not yet been studied. OBJECTIVE: We designed a pilot study to evaluate the use of serum alanine levels as an additional metabolic marker to differentiate the transient effect of circulatory failure from a possible mitochondrial dysfunction. METHODS: We prospectively evaluated 10 newborns with transient lactic acidemia after mild dysoxia, and 10 newborns with recurrent lactic acidemia consecutively diagnosed with a disorder in oxidative phosphorylation. RESULTS: No significant serum alanine level elevation was found in transient lactic acidemia. Increased serum alanine was a sensitive marker in mitochondrial dysfunction. CONCLUSIONS: We propose to measure the serum alanine level in hypotonic newborns with lactic acidemia to facilitate the decision making in further diagnostics and management.

Alanine↗
PubMed2006

Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage.

The aim of the present study was to investigate the neuroprotective effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, against neuron toxicity induced by glucose deprivation, excitatory amino acids and hydrogen peroxide (H(2)O(2)) in cultured rat cerebellar granule cells. Cell membrane damage was measured with a lactate dehydrogenase (LDH) release assay and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess mitochondrial activity, reflecting cell survival. Results showed that honokiol and magnolol alone did not affect mitochondrial function and cell damage, but significantly reversed glucose deprivation-induced mitochondrial dysfunction and cell damage. The glutamate receptor blocker MK-801 and antioxidant vitamin E also provided protection against this damage. Furthermore, honokiol was more potent than magnolol in protecting against glutamate-, N-methyl-D-aspartate (NMDA)- and H(2)O(2)-induced mitochondrial dysfunction. These results demonstrated that the neuroprotective effects of honokiol and magnolol may be related to their anti-oxidative actions and antagonism of excitotoxicity induced by excitatory amino acids, suggesting that both compounds may be potential therapeutic agents for neurodegenerative diseases.

Animals↗
PubMed1999

Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation.

Although an excitotoxic mechanism of neuronal injury has been proposed to play a role in chronic neurodegenerative disorders such as Alzheimer's disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer's disease, we generated PS1 mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Alzheimer's disease. Primary hippocampal neurons from PS1 mutant knock-in mice exhibited increased production of amyloid beta-peptide 42/43 and increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent manner. Neurons expressing mutant PS1 exhibited enhanced calcium responses to glutamate and increased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or activity-dependent neurotrophic factor protected neurons expressing mutant PS1 against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabilized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dysfunction otherwise caused by the PS1 mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutations.

Alzheimer Disease↗
PubMed2003

Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity.

Pulmonary toxicity, including fibrosis, is a serious adverse effect associated with the antidysrhythmic drug amiodarone (AM). We tested the potential usefulness of pirfenidone against AM-induced pulmonary toxicity in the hamster model. Intratracheal AM administration resulted in pulmonary fibrosis 21 days posttreatment, as evidenced by an increased hydroxyproline content and histological damage. Dietary pirfenidone administration (0.5% w/w in chow), for 3 days prior to and continuously after AM, prevented fibrosis and suppressed elevation of pulmonary transforming growth factor (TGF)-beta1 mRNA content at 7 and 21 days post-AM. Protection against AM-induced lung damage was not observed when supplementation with pirfenidone was delayed until 7 days following AM administration, suggesting that alteration of early events in AM lung toxicity is necessary for the protective effect of pirfenidone. Both AM and bleomycin, another pulmonary fibrogen, caused inflammation 24 h after intratracheal dosing, measured as increased lactate dehydrogenase activity, protein content, and cellular alterations in bronchoalveolar lavage fluid, with the response to AM markedly greater than that to bleomycin. Administration of AM, but not bleomycin, also caused whole lung mitochondrial dysfunction, alveolar macrophage death, and an influx of eosinophils into the lung, of which pirfenidone was able to decrease only the latter. We conclude that: (1) AM induces alveolar macrophage death and severe, acute pulmonary inflammation with associated eosinophilia following intratracheal administration; (2) mitochondrial dysfunction may play an early role in AM pulmonary injury; and (3) pirfenidone decreases AM-induced pulmonary fibrosis in the hamster, probably through suppression of TGF-beta1 gene expression.

Acute Disease↗
PubMed1999

Inhibition of mitochondrial oxidative phosphorylation induces hyper-expression of glutamic acid decarboxylase in pancreatic islet cells.

It has been hypothesised that mitochondrial dysfunction in pancreatic beta cells could produce hyper-expression of glutamic acid decarboxylase (GAD), a major autoantigen in insulin-dependent diabetes mellitus (IDDM) (Degli Esposti, M. and Mackay, I.R. Diabetologia 40: 352-356, 1997). Here we report that specific inhibition of mitochondrial respiration enhances the expression of GAD in both foetal mouse pancreatic tissue and hamster HIT-T15 cells. Inhibitors of NADH-ubiquinone oxidoreductase (complex I) seem to be particularly effective in increasing the expression of GAD in both foetal mouse pancreas and HIT-T15 hamster beta cells, especially in the presence of nutrients such as arginine and glucose. These results represent the first evidence that GAD expression is enhanced under conditions that are toxic to pancreatic beta cells, and establish a link between mitochondrial dysfunction and expression of IDDM autoantigens.

Animals↗
PubMed2001

Analysis of the toxic effects of linoleic acid, 12,13-cis-epoxyoctadecenoic acid, and 12,13-dihydroxyoctadecenoic acid in rabbit renal cortical mitochondria.

P450 epoxidation of linoleic acid has been associated with many pathological conditions that often lead to acute renal failure. However, there is only suggestive evidence that linoleic acid monoepoxides and/or linoleic diols directly induce mitochondrial dysfunction. Using isolated rabbit renal cortical mitochondria (RCM), we found that linoleic acid (50 microM) and the linoleic acid monoepoxide, cis-12,13-epoxy-9-octadecenoic acid (12,13-EOA, 50 microM) increased state 4 and oligomycin-insensitive respiration and reduced state 3 and oligomycin-sensitive respiration. Concomitant with these effects, linoleic acid and 12,13-EOA decreased mitochondrial membrane potential (DeltaPsi). In contrast, the hydrolyzed product of 12,13-EOA, 12,13-dihydroxyoctadecenoic acid (12,13-DHOA, 50 microM), had no effect on state 3, state 4, oligomycin-sensitive, and oligomycin-insensitive respiration, and DeltaPsi. Neither linoleic acid or its metabolites altered uncoupled respiration, which suggests that these compounds have no affect on electron transport chain in RCM. Nucleotides such as ATP (0.5 mM) and GDP (0.5 mM) partially prevented the decrease in DeltaPsi but did not attenuate the increase in oligomycin-insensitive respiration after exposure to linoleic acid (50 microM) and 12,13-EOA (50 microM). These results demonstrate that linoleic acid metabolism to the 12,13-DHOA is a detoxification pathway that prevents mitochondrial dysfunction in RCM. The increase in state 4 respiration concomitant with decreases in state 3 respiration and DeltaPsi suggest that, in addition to uncoupling effects, linoleic acid and 12,13-EOA may have other effects, such as alterations of mitochondrial membranes. The inability of ATP and GDP to fully attenuate the uncoupling effects of linoleic acid and 12,13-EOA suggests that these effects are mediated through a nucleotide-independent mechanism.

Adenosine Triphosphate↗
PubMed2005

Nitric oxide induces osteoblast apoptosis through a mitochondria-dependent pathway.

Osteoblasts contribute to bone remodeling. Nitric oxide can regulate osteoblast activities. In this study, we attempted to evaluate the pathophysiological effects of nitric oxide on osteoblasts and its possible mechanism using neonatal rat calvarial osteoblasts as the experimental model. Exposure of osteoblasts to sodium nitroprusside, a nitric oxide donor, decreased alkaline phosphatase activities and cell viability in a concentration- and time-dependent manner. Apoptotic analysis revealed that sodium nitroprusside time-dependently increased the percentages of osteoblasts undergoing apoptosis. Administration of sodium nitroprusside reduced the mitochondrial membrane potential of osteoblasts. In parallel with the mitochondrial dysfunction, levels of intracellular reactive oxygen species and cytochrome c were significantly elevated following sodium nitroprusside administration. Exposure of osteoblasts to sodium nitroprusside significantly increased caspase-3 activity. Results of this study show that nitric oxide, decomposed from sodium nitroprusside, can induce osteoblast apoptosis through a mitochondrion-dependent cascade that causes mitochondrial dysfunction, release of intracellular reactive oxygen species and cytochrome c from mitochondria to cytoplasm, and activation of caspase-3.

Alkaline Phosphatase↗