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Results for “mitochondrial dysfunction”

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At least 307 records · Page 17Linked to original sources

PubMed2003

Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia.

Ischemia/reperfusion of heart causes contractile dysfunction, necrosis and/or apoptosis and is a major cause of human death, but the molecular mechanisms are unclear. We show that ischemia alone (without reperfusion) is sufficient to induce apoptosis and mitochondrial dysfunction, and we have investigated the mechanism responsible; 30 and 60 min stop-flow ischemia in Langendorff-perfused rat hearts induced progressive (a). release of cytochrome c from mitochondria to cytosol, (b). inhibition of the mitochondrial respiratory functions, (c). activation of caspase-3-like protease activity and (d). DNA strand breaks (however, only 2% of myocyte nuclei were TUNEL positive at 60 min). Fifteen minutes pre-perfusion of hearts with cyclosporin A, an inhibitor of mitochondrial-permeability transition (MPT), largely prevented all these ischemic changes. Pre-perfusion of hearts with FK506, an inhibitor of calcineurin, caused no protection. Pre-perfusion with DEVD-CHO, an inhibitor of caspase-3-like proteases, completely prevented ischemia-induced DNA strand breaks, but only partially blocked cytochrome c release and mitochondrial respiratory inhibition. Reperfusion of hearts after 30 min ischemia further stimulated caspase activity and nuclear apoptosis. We conclude that ischemia-induced MPT causes release of cytochrome c, which then activates the caspases that execute apoptosis and feedback to cause further cytochrome c release. The MPT-induced cytochrome c release is also largely responsible for the ischemic respiratory inhibition, which might contribute to contractile dysfunction or necrosis at reperfusion.

Animals↗

PubMed2006

Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation.

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.

AMP-Activated Protein Kinases↗

PubMedDate not supplied

Asbestos-induced alveolar epithelial cell apoptosis: role of mitochondrial dysfunction caused by iron-derived free radicals.

Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-inducedAEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (delta(psi)m) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces delta(psi)m after a 4 h exposure period. Further, the delta(psi)m after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell delta(psi)m and attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell delta(psi)m after 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos.

Apoptosis↗

PubMed2004

In vivo TNF-alpha inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure.

Heart failure is associated with increased myocardial expression of TNF-alpha. However, the role of TNF-alpha in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF-alpha to myocardial mitochondrial dysfunction, oxidative stress, and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathological processes. Male mongrel dogs were randomly assigned (n = 10 each) to 1) normal controls; 2) chronic pacing (250 beats/min for 4 wk) with concomitant administration of etanercept, a soluble p75 TNF receptor fusion protein, 0.5 mg/kg subcutaneously twice weekly; 3) chronic pacing with administration of saline vehicle. Mitochondrial function was assessed by left ventricular (LV) tissue mitochondrial respiratory enzyme activities. Oxidative stress was assessed with aldehyde levels, and apoptosis was quantified by photometric enzyme immunoassay for cytoplasmic histone-associated DNA fragments and terminal deoxynucleotide transferase-mediated nick-end labeling (TUNEL) assays. LV activity levels of mitochondrial respiratory chain enzyme complex III and V were reduced in the saline-treated dogs and restored either partially (complex III) or completely (complex V) in the etanercept-treated dogs. Aldehyde levels, DNA fragments, and TUNEL-positive cells were increased in the saline-treated dogs and normalized in etanercept-treated dogs. These changes were accompanied by an attenuation of LV dilatation and partial restoration of ejection fraction. Our data demonstrate that TNF-alpha contributes to progressive LV dysfunction in pacing-induced heart failure, mediated in part by a local impairment in mitochondrial function and increase in oxidative stress and myocyte apoptosis.

Animals↗

PubMed2001

Congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy: a possible relation with mitochondrial dysfunction.

We report the case of a fetus aborted at gestation week 20 because of hydranencephalic-hydrocephalic syndrome. The fetus was the third pregnancy of a nonconsanguineous couple whose first child exhibited congenital hydranencephalic-hydrocephalic syndrome associated with muscle histology findings consistent with mitochondrial cytopathy and deficiency of complexes III and IV of the respiratory chain and whose second pregnancy had terminated in an elective abortion on detection of progressive hydrocephalus at gestation week 19. The third pregnancy had a normal course according to obstetric and ultrasonography examinations performed at gestation weeks 5, 10, and 15, and negative results were obtained in standard serologic and polymerase chain reaction (PCR) tests for prenatal infections of the mother. However, the ultrasonography examination at gestation week 18 revealed hydrocephalus, in response to which the parents requested an abortion, which was performed at gestation week 20; the fetus was male and with no evident external malformations. Histopathologic studies of the brain and medulla oblongata revealed proliferative vasculopathy (glomeruloid vessels, intracytoplasmic inclusions, and microcalcifications) and intracytoplasmic inclusions in the voluntary muscle. Microbiologic and PCR tests of hepatic and spleen tissue were negative for prenatal infections. In view of the precedent of a sister with mitochondrial dysfunction, these findings raise the pos sibility that at least some cases of familial syndrome of congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy can be attributed to alterations in the mitochondrial respiratory chain.

Abortion, Induced↗

PubMed1999

Hepatotoxicity due to mitochondrial dysfunction.

Mitochondria are involved in fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, which provide most of the cell energy. Mitochondria are also the main source of reactive oxygen species in the cell and are involved in cell demise through opening of the mitochondrial permeability transition pore. It was therefore to be expected that mitochondrial dysfunction could be a major mechanism of drug-induced liver disease. Microvesicular steatosis (which may cause liver failure, coma, and death) is the consequence of severe impairment of mitochondrial beta-oxidation. Endogenous compounds (such as cytokines or female sex hormones) or xenobiotics (including toxins such as ethanol and drugs such as aspirin, valproic acid, ibuprofen, or zidovudine) can inhibit beta-oxidation directly or through a primary effect on the mitochondrial genome or the respiratory chain itself. In some patients, infections and cytokines, or inborn errors of beta-oxidation enzymes or the mitochondrial genome, may favor the appearance of drug-induced microvesicular steatosis. Nonalcoholic steatohepatitis may develop under conditions causing prolonged, microvesicular, and/or macrovacuolar steatosis. In this condition, chronic impairment of mitochondrial beta-oxidation (causing steatosis) and the respiratory chain (increasing the production of ROS) lead to lipid peroxidation, which, in turn, may cause the diverse lesions of steatohepatitis, namely, necrosis, inflammation, Mallory's bodies, and fibrosis. Finally, mitochondria are involved in several forms of drug-induced cytolytic hepatitis, through inhibition or uncoupling of respiration or through a drug-induced or reactive metabolite-induced mitochondrial permeability transition. The latter effect commits hepatocytes to either apoptosis or necrosis, depending on the number of organelles that have undergone the permeability transition.

Animals↗

PubMed2006

Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease.

Oxidative stress and hepatic mitochondria play a role in the pathogenesis of nonalcoholic fatty liver disease. The aim of the present study was to evaluate the role of hepatic mitochondrial dysfunction and oxidative stress in the pathogenesis of the disease. Fatty liver was induced in Wistar rats with a choline-deficient diet (CD; N = 7) or a high-fat diet enriched with PUFAs-omega-3 (H; N = 7) for 4 weeks. The control group (N = 7) was fed a standard diet. Liver mitochondrial oxidation and phosphorylation were measured polarographically and oxidative stress was estimated on the basis of malondialdehyde and glutathione concentrations. Moderate macrovacuolar liver steatosis was observed in the CD group and mild liver steatosis was observed in the periportal area in the H group. There was an increase in the oxygen consumption rate by liver mitochondria in respiratory state 4 (S4) and a decrease in respiratory control rate (RCR) in the CD group (S4: 32.70 +/- 3.35; RCR: 2.55 +/- 0.15 ng atoms of O2 min-1 mg protein-1) when compared to the H and control groups (S4: 23.09 +/- 1.53, 17.04 +/- 2.03, RCR: 3.15 +/- 0.15, 3.68 +/- 0.15 ng atoms of O2 min-1 mg protein-1, respectively), P < 0.05. Hepatic lipoperoxide concentrations were significantly increased and the concentration of reduced glutathione was significantly reduced in the CD group. A choline-deficient diet causes moderate steatosis with disruption of liver mitochondrial function and increased oxidative stress. These data suggest that lipid peroxidation products can impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial reactive oxygen species. These findings are important in the pathogenesis of nonalcoholic fatty liver disease.

Animals↗

PubMed2005

Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis.

Multiple Sclerosis is the most common inflammatory demyelinating disease of the central nervous system and is the leading cause of non traumatic neurological disability in young adults. In recent years it has become increasingly evident that axonal degeneration is a key player in the pathogenesis of disability in MS but the mechanisms that lead to axonal damage are not fully understood. It seems likely that the causes of axonal damage vary at different stages of the disease and several theories have evolved that address the mechanisms leading to axonal loss in the acute stages of demyelination. There has been relatively little attention given to investigation of the mechanisms involved in chronic axonal loss in the progressive stages of MS. We propose a hypothesis that mitochondria play a key role in this chronic axonal loss. Following demyelination there is redistribution of sodium channels along the axon and mitochondria are recruited to the demyelinated regions to meet the increased energy requirements necessary to maintain conduction. The mitochondria present within the chronically demyelinated axons will be functioning at full capacity. The axon may well be able to function for many years due to these adaptive mechanisms but we propose that eventually, despite antioxidant defences, free radical damage will accumulate and mitochondrial function will become compromised. ATP concentration within the axon will decrease and the effect on axonal function will be profound. The actual cause of cell death could be due to a number of mechanisms related to mitochondrial dysfunction including failure of ionic homeostasis, calcium influx, mitochondrial mediated cell death or impaired axonal transport. Whatever the cause of axonal loss our hypothesis is that mitochondria are central to this process. We explore steps to test this hypothesis and discuss the possible therapeutic approaches which target the mitochondrial mechanisms that may contribute to chronic axonal loss.

Adult↗

PubMed2005

Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: implications for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of PD is not clearly understood, oxidative stress and mitochondrial dysfunction are thought to play a role. We have previously suggested tetrahydrobiopterin (BH4), an obligatory cofactor for the dopamine synthesis enzyme tyrosine hydroxylase and present selectively in monoaminergic neurons in the brain, as an endogenous molecule that contributes to the dopaminergic neurodegeneration. In the present study, we show that BH4 leads to inhibition of activities of complexes I and IV of the electron transport chain (ETC) and reduction of mitochondrial membrane potential. BH4 appears to be different from rotenone and MPP(+), the synthetic compounds used to generate Parkinson models, in its effect on complex IV. BH4 also induces the release of mitochondrial cytochrome c. Pretreatment with the sulfhydryl antioxidant N-acetylcysteine or the quinone reductase inducer dimethyl fumarate prevents the ETC inhibition and cytochrome c release following BH4 exposure, suggesting the involvement of quinone products. Together with our previous observation that BH4 leads to generation of oxidative stress and selective dopaminergic neurodegeneration both in vitro and in vivo via inducing apoptosis, the mitochondrial involvement in BH4 toxicity further suggests possible relevance of this endogenous molecule to pathogenesis of PD.

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

PubMed2002

Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons.

Beta-amyloid deposition and compromised energy metabolism both occur in vulnerable brain regions in Alzheimer's disease. It is not known whether beta-amyloid is the cause of impairment of energy metabolism, nor whether impaired energy metabolism is specific to neurons. Our results, using primary neuronal cultures, show that 24-h incubation with A beta(25-35) caused a generalized decrease in the specific activity of mitochondrial enzymes per milligram of cellular protein, induced mitochondrial swelling, and decreased total mitochondrial number. Incubation with A beta(25-35) decreased ATP concentration to 58% of control in neurons and 71% of control in astrocytes. Levels of reduced glutathione were also lowered by A beta(25-35) in both neurons (from 5.1 to 2.9 nmol/mg protein) and astrocytes (from 25.2 to 14.9 nmol/mg protein). We conclude that 24-h treatment with extracellular A beta(25-35) causes mitochondrial dysfunction in both astrocytes and neurons, the latter being more seriously affected. In astrocytes mitochondrial impairment was confined to complex I inhibition, whereas in neurons a generalized loss of mitochondria was seen.

Amyloid beta-Peptides↗

PubMed1997

Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents.

A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, 1-beta-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (delta psi m) that precedes nuclear DNA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin in vitro. Circulating tumor cells from patients receiving chemotherapy in vivo also demonstrate a delta psi m disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-XL protects against chemotherapy-induced apoptosis, at both the level of the mitochondrial dysfunction preceding nuclear apoptosis and the level of late nuclear apoptotic events. Bcl-2-mediated inhibition of ceramide-induced delta psi m disruption is observed in normal as well as anucleate cells, indicating that bcl-2 acts on an extranuclear pathway of apoptosis. In contrast to Bcl-2 and Bcl-XL, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced delta psi m disruption and apoptosis, although cytokine response modifier A does prevent the delta psi m collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, delta psi m disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and delta psi m is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.

Adult↗

PubMed2002

beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine.

In Alzheimer's disease (AD), loss of synapses exceeds neuronal loss and some evidence suggests a role of beta-amyloid protein (Abeta) in synaptic degeneration through a mechanism which may involve intraneuronal Ca2+ dyshomeostasis. Emerging evidence points to the participation of the internal Ca2+ stores in the pathophysiology of neurodegeneration in AD. To test the involvement of intrasynaptic Ca2+ mobilization in A toxicity, we explored the role of ryanodine receptor activation in rat cortical synaptosomes taken as a model system for the central presynapses. Evaluation of synaptosomal mitochondrial redox capacity was assessed by the MTT reduction technique, and ultrastructural changes of synaptosomes after exposure to Abeta and ryanodine were evaluated by electron microscopy. Our results show that Abeta potentiates mitochondrial dysfunction in the presence of ryanodine and induces morphological changes consisting of mitochondrial swelling and intense small synaptic vesicles depletion. These changes were accompanied by a reduction in the content of synaptophysin and actin proteins. The reduction of actin immunoreactivity was reversed in the presence of a wide range caspase inhibitors, suggesting the activation of synaptic apoptotic mechanisms.

Amyloid beta-Peptides↗

PubMed2002

A novel defense system of mitochondria in mice and human subjects for preventing expression of mitochondrial dysfunction by pathogenic mutant mtDNAs.

Recently, we generated mtDNA-based disease mice (mito mice) by introduction of respiration-deficient mitochondria possessing pathogenic mutant mtDNA with a 4696 bp deletion (deltamtDNA4696) from somatic cells into mouse zygotes. Mito mice and cytochrome c oxidase (COX) electronmicrographs, that could identify the respiration enzyme activity at individual mitochondrial levels, enabled precise investigation of the pathogenesis of deltamtDNA4696. All the observations represented unambiguous evidence for the presence of extensive and continuous exchange of genetic contents between mitochondria. Thus, the inter-mitochondrial interaction could correspond to a very unique and effective defense system of the highly oxidative organelles for preventing mice and human subjects from expressing mitochondrial dysfunction caused by mtDNA lesions, which have been continuously created by oxidative stresses during aging. Here, we would like to propose a new hypothesis on mitochondrial biogenesis, 'the interaction theory of mammalian mitochondria': mitochondria exchange genetic contents, and thus lose individuality and function as a single dynamic cellular unit.

Journal Article↗

PubMed2025

Mitochondrial dysfunction in MED13 variant-associated disease: a case of infantile spasms, cardiomyopathy and hepatomegaly.

Here we report a de novo heterozygous MED13 variant (c.2503C>T, p.Pro835Ser) in an infant presenting with infantile spasms, hypertrophic cardiomyopathy and hepatomegaly. Autopsy revealed mitochondrial abnormalities in cardiac and hepatic tissues, with reduced respiratory chain complex activity. This is the first case report linking a MED13 variant to systemic mitochondrial dysfunction, suggesting a novel pathogenic mechanism.

Journal Article↗

PubMed2000

Very low levels of the mtDNA A3243G mutation associated with mitochondrial dysfunction in vivo.

We studied mitochondrial function in vivo in 2 brothers harboring the mitochondrial DNA A3243G mutation by using magnetic resonance spectroscopy. One brother presented with recurrent strokes and had a mitochondrial respiratory chain complex I defect, with 85% A3243G mutation in his quadriceps. The maximum rate of mitochondrial ATP production in his calf, measured in vivo, was reduced to 21% of the normal mean value. The second brother had mild exercise intolerance, normal muscle histochemistry, and normal respiratory chain activity in vitro. Despite a level of the A3243G mutation of only 5.95% (SD, 4.45; range, 0.7-16.1%) within single muscle fibers from the gastrocnemius muscle, the maximum rate of mitochondrial ATP production in his calf, measured in vivo, was reduced to 35% of the normal mean value. These findings suggest that there may not be a clear genetic threshold level for the expression of the A3243G mutation in skeletal muscle in vivo.

Adult↗

PubMed1996

Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha.

Kupffer cells have been implicated in playing an important role in the pathogenesis of endotoxemia-associated liver injury. The present study was designed to investigate whether Kupffer cell-derived mediators alter the mitochondrial oxidative phosphorylation of hepatocytes in the endotoxemic condition. Liver cells were isolated from male Wistar rats. Oxidative phosphorylation was monitored as the fluorescence of rhodamine 123 (Rh123), which is the fluorescent cationic dye used to indicate mitochondrial energy synthesis. Two hours after coculture of hepatocytes with lipopolysaccharide (LPS)-pretreated Kupffer cells, a marked decrease in hepatocyte rhodamine 123 fluorescence was observed. The hepatocyte mitochondrial dysfunction was attenuated by the addition of either N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, or aminoguanidine, an inducible-type of NO synthase inhibitor, to the culture medium of cocultures, to the pretreatment of LPS-activated Kupffer cells with antisense oligodeoxynucleotides against iNOS messenger RNA (mRNA), or to tumor necrosis factor alpha (TNF-alpha) mRNA. Four hours after the coculture, hepatocyte Rh123 fluorescence further decreased, and an iNOS induction as well as an increased NO production were observed in hepatocytes that were cocultured with LPS-pretreated Kupffer cells. The membrane barrier dysfunction of hepatocytes, indicated by propidium iodide staining, was also induced by a 4-hour coculture with LPS-pretreated Kupffer cells. These late-phase changes were inhibited either by the pretreatment of hepatocytes with antisense oligodeoxynucleotides against iNOS mRNA or by treatments that are effective in the early phase (within 2 hours). Incubation with recombinant rat TNF-alpha decreased hepatocyte Rh123 fluorescence within 2 hours. Thus, the present study suggests that NO and TNF-alpha released from LPS-pretreated Kupffer cells directly inhibit the hepatocyte mitochondrial function in the early phase, and then NO synthesized by TNF-alpha-induced hepatocyte iNOS causes lethal hepatocyte injury, characterized by diminished mitochondrial energization and membrane barrier function in the late phase.

Animals↗

PubMed2006

Perihematomal mitochondrial dysfunction after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Recent measurements in intracerebral hemorrhage (ICH) patients suggest a primary reduction in brain metabolism is responsible for reduced cerebral blood flow and low oxygen extraction surrounding the hematoma. We sought to determine whether reduced mitochondrial respiratory function could account for reduced metabolic demand in ICH patients. METHODS: Brain-tissue samples from 6 patients with acute spontaneous ICH and 6 control patients undergoing brain resection for management of seizure were evaluated. Only tissue removed from the brain adjacent to the hematoma was studied. Specimens were collected in the operating room; mitochondrial studies were begun within 1-hour. Mitochondrial oxygen consumption was measured after the addition of pyruvate, malate, and ADP, followed by oligomycin and carbonylcyanide. RESULTS: The ICH patients ranged in age from 40 to 54 years; 2 were female and half black. Hemorrhages were located in the temporal lobe (3), cerebellum (2) and parietal lobe (1). The average State 3 (active) O2 consumption for mitochondria from ICH patients was approximately 40% lower than that of control patients ( CONTROLS: 129+/-39 versus ICH: 76+/-28 nmol O2/min per mg protein). With increasing time from hemorrhage to testing there was a progressive decline in State 3 respiration. Reduced State 3 respiration was evident even at 6 hours, whereas at 72 hours, there was essentially no O2 consumption. CONCLUSIONS: These data support the hypothesis that mitochondrial dysfunction and not ischemia is responsible for reduced oxygen metabolism in ICH. They point to a new direction for investigation and development of therapeutic interventions for ICH patients.

Adenosine Triphosphate↗

PubMed1988

Effect of the alpha 1-blocker bunazosin on reperfusion-induced mitochondrial dysfunction in canine hearts.

The effect of the alpha 1-blocker 4-amino-2-(4-butyryl-hexahydro-1H-1,4-diazepin-1-yl) -6,7-dimethoxy-quinazoline (bunazosin, E-643, Detantol) on reperfusion injury was investigated. 43 anesthetized dogs were divided into two groups: the control group (n = 30) and the bunazosin group (n = 13). 15 min after premedication with physiological saline for the control group, or the alpha 1-blocker bunazosin 0.5 mg/kg for the bunazosin group, the left anterior descending coronary artery was occluded for 15 min and then reperfused for 5 min. Heart mitochondria were prepared from both the normal and reperfused areas. Mitochondria function and their Ca2+ content were measured by polarography and atomic absorption, respectively. Mitochondrial phospholipase activity was measured by high performance liquid chromatography. Nine dogs (30%) of the control group developed reperfusion arrhythmias. None of those pretreated with bunazosin developed arrhythmias. Although mitochondrial dysfunction was observed in the reperfused area in each group, more severe dysfunction was observed in dogs with arrhythmias in the control group. Mitochondrial Ca2+ content in the reperfused area in dogs with arrhythmias increased significantly compared with that in the normal area. Phospholipase activity in the reperfused area in dogs with arrhythmias also increased significantly, but no significant elevation of phospholipase activity was observed in dogs without arrhythmias in both the control and bunazosin groups. These results indicate that reperfusion injury might be closely related to activation of phospholipase linked with alpha 1-adrenergic response.

Adrenergic alpha-Antagonists↗