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PubMed2006

MitoP2: the mitochondrial proteome database--now including mouse data.

The MitoP2 database (http://www.mitop.de) integrates information on mitochondrial proteins, their molecular functions and associated diseases. The central database features are manually annotated reference proteins localized or functionally associated with mitochondria supplied for yeast, human and mouse. MitoP2 enables (i) the identification of putative orthologous proteins between these species to study evolutionarily conserved functions and pathways; (ii) the integration of data from systematic genome-wide studies such as proteomics and deletion phenotype screening; (iii) the prediction of novel mitochondrial proteins using data integration and the assignment of evidence scores; and (iv) systematic searches that aim to find the genes that underlie common and rare mitochondrial diseases. The data and analysis files are referenced to data sources in PubMed and other online databases and can be easily downloaded. MitoP2 users can explore the relationship between mitochondrial dysfunctions and disease and utilize this information to conduct systems biology approaches on mitochondria.

Animals↗

PubMedDate not supplied

Hepatotoxicity in rat following administration of valproic acid: effect of L-carnitine supplementation.

The effect of prolonged administration (7 days) of valproate (VPA, 500 mg/kg/day), or VPA (500 mg/kg/day) with L-carnitine (200 mg/kg/day) on blood carnitine levels and the appearance of liver mitochondria were assessed in the rat. VPA-treated rats showed hypocarnitinemia and enlarged mitochondria when compared with saline-injected control rats. In rats treated with both VPA and L-carnitine, serum and liver carnitine levels were increased by the L-carnitine supplement and the liver mitochondria were not enlarged. L-Carnitine supplement in VPA-medicated patients seems to prevent hepatotoxicity, especially mitochondrial dysfunction.

Animals↗

PubMed2005

Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?

The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Polycyclic phenols, estrogens and neuroprotection: a proposed mitochondrial mechanism.

Polycyclic phenols, including the estrogens, have been shown to be potent neuroprotectants in a variety of cellular and animal model systems. Although classical estrogen receptor interactions and consequent responses play a role in certain circumstances, the neuroprotective activity of polycyclic phenols that do not interact with estrogen receptors ERalpha or ERbeta is more likely to be through non-genomic mechanism(s). We propose here that such non-feminizing polycyclic phenols exert their protective effects at least in part by stabilizing mitochondria, preventing apoptotic and/or necrotic forms of cell death that are associated with mitochondrial dysfunction. Consistent with this mitochondrial model and the available data, these compounds protect neurons and other cell types from a wide variety of pathologically relevant stressors.

Adenosine Triphosphate↗

PubMed1991

Pentachlorobutadienyl-L-cysteine (PCBC) toxicity: the importance of mitochondrial dysfunction.

The relationship between the covalent binding, uptake, and toxicity produced by pentachlorobutadienyl-L-cysteine (PCBC) was examined in rabbit renal proximal tubules (RPT), renal basolateral membrane vesicles, and isolated renal cortical mitochondria. Renal proximal tubules rapidly metabolized PCBC to a reactive intermediate that bound to tubular protein. Approximately 70-90% of PCBC found in the cell at any given time was bound to protein. PCBC initially uncoupled oxidative phosphorylation, followed by a 45% reduction of state 3 respiration and a 90% decrease in cellular adenosine triphosphate (ATP) levels. These events preceded cell death. Isolated mitochondria also metabolized PCBC to a reactive intermediate that bound to mitochondrial protein and initiated mitochondrial toxicity. These results show that PCBC-induced mitochondrial dysfunction occurred as a result of mitochondrial bioactivation and that the mitochondrion is the critical subcellular target in PCBC toxicity. Aminooxyacetic acid (AOAA), an inhibitor of cysteine conjugate beta-lyase, reduced the covalent binding of PCBC-equivalents to tubular protein by approximately 90% and decreased but did not prevent the toxic effects produced by PCBC on RPT respiration and cellular ATP levels. AOAA delayed but had no effect on the overall extent of cell death produced by PCBC. The protective effect of AOAA was independent of any effects on PCBC uptake. These results show that AOAA decreased but did not prevent the metabolism of PCBC by cysteine conjugate beta-lyase. The partial inhibition of PCBC metabolism, and hence, PCBC-induced cell death by AOAA, may be related to limited concentrations of AOAA within the tubule cell or mitochondria.

Adenosine Triphosphate↗

PubMed1996

Calcium-related damage in ischemia.

The objective of this hypothesis article is to review evidence supporting a role for calcium in mediating ischemic brain damage, and to present data which puts mitochondrial dysfunction in the center of interest. The assumptions/postulates put forward, relating to global/forebrain and to focal ischemia, are as follows. (1) In brief ischemia of the global/forebrain type neuronal necrosis, particularly in the CA1 sector of the hippocampus, is conspicuously delayed. It is postulated that the initial events during ischemia, and in the immediate recirculation period, lead to a perturbation of cell calcium homeostasis, with a gradual postischemic rise in the free cytosolic calcium concentration (Ca2+i). When the latter reaches a certain limiting value mitochondria start accumulating calcium. It is hypothesized that intramitochondrial calcium accumulation triggers a permeability transition of the inner mitochondrial membrane (MPT), leading to production of reactive oxygen species, release of calcium, and an increase in the cytosol calcium concentration of a potentially adverse nature. (2) If ischemia of this "cardiac arrest" type is prolonged, or complicated by preischemic hyperglycemia, neuronal necrosis is enhanced and pan-necrotic lesions appear. Such insults are known to cause rapidly developing mitochondrial failure, but the involvement of calcium has not yet been demonstrated. (3) In focal ischemia, core tissues probably suffer a metabolic insult similar to that affecting brain tissues in global/forebrain ischemia. Thus, calcium influx and calcium overload of mitochondria are predictable, but available data only demonstrate rapidly developing, secondary energy failure, mitochondrial dysfunction, and enhanced influx of 45Ca. Thus, although secondary mitochondrial failure has been proved, a causative link between calcium influx and bioenergetic failure remains to be proved. Perifocal, penumbral tissues are exposed to spontaneously occurring depolarisation waves, leading to cellular efflux of K+ and influx of Ca2+. The latter may lead to gradual mitochondrial calcium overload triggering a MPT, and cell death. Although conclusive evidence has not yet been presented available results suggest a link between calcium influx, mitochondrial overload, and cell death.

Animals↗

PubMed2006

Mechanisms of disease: apoptosis in heart failure--seeing hope in death.

Apoptosis or programmed cell death is an evolutionarily conserved process of cell death, wherein cells die without provoking significant inflammatory response. There is convincing evidence that apoptosis contributes to the progression of heart failure. Apoptosis occurs through a cascade of subcellular events including cytochrome c release into the cytoplasm and activation of proteolytic caspases. Activated caspases lead to fragmentation of cytoplasmic proteins, including contractile apparatus, to a variable extent. It is proposed that the release of cytochrome c from mitochondria and contractile protein loss in living heart muscle cells contributes to systolic dysfunction. Interestingly, despite extensive changes in the cytoplasm, nuclear damage, which is the final event in apoptosis, is rather infrequent in the failing heart. Since the nucleus remains unaffected and the genetic blueprint intact in cells with interrupted apoptosis, these heart muscle cells might be amenable to cytoplasmic reconstitution. This process of 'apoptosis interruptus' could allow development of novel strategies to reverse or attenuate heart failure.

Animals↗

PubMed1997

Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats.

In the present study, a severe traumatic brain injury (TBI) was produced over the right parietal cortex of rats using the controlled cortical impact injury (CCII) model. TBI perturbed calcium homeostasis and impaired electron transfer and energy coupling activities of forebrain mitochondria isolated from injured hemispheres with a maximal injury at 12-72 h. Efficacy of the blood-brain barrier penetrating antioxidant U-101033E on TBI-induced mitochondrial impairment was evaluated. In the dose-response experiment, two i.v. boluses (vehicle or 1-10 mg/kg of U-101033E) were administered at 5 min and 2h post-TBI. Forebrain mitochondria from each hemisphere were examined at 12 h post-injury. With respect to forebrain mitochondrial dysfunction, the drug showed a bell-shaped dose-response curve with an optimal dose of 3 mg/kg (n = 5, p < 0.05 vs. vehicle). In the time-course experiment, two i.v. boluses of 3 mg U-101033E/kg (the optimal dose) were given at 5 min and 2 h post-injury and forebrain mitochondria were examined at 6 h-14 days post-injury. U-101033E significantly restored electron transfer, energy coupling capacity, and Ca2+ transport capacity during 6 h to 14 days post-injury. Our data indicate that the antioxidant U-101033E administered post-injury at proper dosage can effectively restore TBI-induced mitochondrial dysfunction and support the contention that oxidative stress plays an important role in the pathogenesis of TBI.

Animals↗

PubMed2005

Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function.

Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl-beta-cyclodextrin can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.

Adenosine Triphosphate↗

PubMed2006

Mitochondrial alterations in Alzheimer's disease.

Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimer's disease and other neurodegenerative disorders. Mitochondrial dysfunction is also a hallmark of beta peptide induced neuronal toxicity in Alzheimer's disease. A general change in glucose utilization, increased oxidative stress, and Ca;{2+} deregulation are additional metabolic defects in the AD brain that may also be associated with defective mitochondrial function the result is a cycle of increased mitochondrial dysfunction causing increased oxidative damage until the cellular energy supply falls below the threshold for cellular survival. In a series of studies on the morphological and morphometric estimation of mitochondria in Alzheimer's disease, by electron microscopy we noticed substantial morphological and morphometric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the climbing fibers, the thalamus, the globus pallidus, the red nucleus and the locus coeruleus. The morphological alterations consisted of considerable changes of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits, though they were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship between the site and extent of mitochondrial abnormalities and the synaptic alterations suggests an intimate and early association between these features in Alzheimer's disease.

Alzheimer Disease↗

PubMed1977

Ultrastructural and biochemical effects of prolonged oral arsenic exposure on liver mitochondria of rats.

This investigation was undertaken to further delineate the subcellular manifestations of arsenic toxicity following chronic exposure using combined ultrastructural and biochemical techniques. Male rats were given access to deionized drinking water solutions containing 0, 20, 40, or 85 arsenic as arsenate (As(+5)) for 6 weeks. In situ swelling of liver mitochondria was the most prominent ultrastructural change observed. Mitochondrial respiration studies indicated decreased state 3 respiration and respiratory control ratios (RCR) for pyruvate/malate but not succinate mediated respiration. Specific activity of monoamine oxidase which is localized on the outer mitochondrial membrane showed increases of up to 150% of control and cytochrome-C oxidase which is localized on the inner mitochondrial membrane showed increases in specific activity of 150-200%. Activity of malate dehydrogenase which is localized in the mitochondrial matrix was unchanged at any dose level. These studies indicate that decreased mitochondrial respiration is only one aspect of arsenic toxicity to this organelle. Marked arsenic-mediated perturbation of important enzyme systems localized in mitochondria which participate in the control of respiration and other normal mitochondrial functions are also important manifestations of cellular dysfunction.

Administration, Oral↗

PubMed1981

Mechanism of chlorpromazine-induced arrhythmia -- arrhythmia and mitochondrial dysfunction.

In this study, we investigated the mechanism of the arrhythmogenic action of chlorpromazine (CPZ). Thirty-two anesthetized mongrel dogs were used. In each, the chest was opened and a stimulating electrode was attached to the apex of the left ventricle and the ventricular multiple response threshold (VMRT) was measured. The carotid artery was cannulated to measure aortic pressure. The dogs were divided into four groups, and the time course of VMRT, blood pressure, and heart rate were determined. All groups were placed under observation for 30 min after CPZ infusion. In the control group, only saline (2ml/kg) was infused; CPZ group: CPZ (Img/kg) was infused 10 min after saline (2ml/kg) infusion; CoQ10 group: Coenzyme Q10 (CoQ10) (5mg/kg) was infused 10 min before CPZ (Img/kg) infusion; FAD group: Flavin-adenine-dinucleotide (FAD) (2mg/kg) was infused 10 min before CPZ (Img/kg) infusion. In each group, myocardial mitochondria were prepared 30 min after CPZ infusion. The mitochondrial functions, respiratory control index, AdP/O, State III rate of oxygen consumption, and activities of two segments of the electron-transport chain (NADH leads to CoQ leads to cyt.c and cyt.c leads to cyt.a,a3 leads to O2) were measured separately. Ca++--binding activity of the mitochondria was also determined. CPZ administration decreased VMRT and blood pressure, and caused mitochondrial dysfunction which derived from a disturbance in the first segment of the electron transport chain. Decreased Ca++--binding activity was observed when mitochondrial function was disturbed. CoQ10 prevented significantly the decrease in VMRT and the disturbance of mitochondrial function induced by CPZ, but did not prevent the hypotensive effect of CPZ. FAD prevented not only the decrease in VMRT and the disturbance of mitochondrial function, but also the hypotensive effect of CPZ. These results suggest that the decrease in VMRT is closely related to mitochondrial dysfunction induced by CPZ. Moreover, it is suggested that the arrhythmogenic effect of CPZ is derived from the decreased mitochondrial Ca++--binding activity.

Animals↗

PubMed2005

Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis.

It is now widely accepted that oxidant stress and the ensuing endothelial dysfunction play a key role in the pathogenesis of atherosclerosis and cardiovascular diseases. The mitochondrial respiratory chain is the major source of reactive oxygen species as byproducts of normal cell respiration. Mitochondria may also be important targets for reactive oxygen species, which may damage mitochondrial lipids, enzymes and DNA with following mitochondrial dysfunction. Free cholesterol, oxidized low-density lipoprotein and glycated high-density lipoprotein are further possible causes of mitochondrial dysfunction and/or apoptosis. Moreover, in patients with mitochondrial diseases, vascular complications are commonly observed at an early age, often in the absence of traditional risk factors for atherosclerosis. We propose that mitochondrial dysfunction, besides endothelial dysfunction, represents an important early step in the chain of events leading to atherosclerotic disease.

Animals↗

PubMed2002

iNOS enhances rat intestinal apoptosis after ischemia-reperfusion.

The aim of this study was to demonstrate (i) the role of iNOS (inducible nitric oxide synthase) on apoptosis in the rat intestinal mucosa after ischemia-reperfusion, and (ii) the effect of iNOS on the release of cytochrome c from mitochondria. The superior mesenteric artery was occluded for 60 min and was followed by a 60 min reperfusion. Rats were pretreated with an intraperitoneal injection of the following iNOS inhibitors: N-nitro-L-arginine methyl ester, aminoguanidine, and (1S,5S,6R,7R)-7- chloro-3-imino-5-methyl-2-azabicyclo [4. 1. 0] heptane hydrochloride (ONO-1714). Apoptosis was evaluated and NO(X) in the portal vein was assayed. The amount of iNOS, caspase-3, and cytochrome c were determined by a Western blot analysis. Intestinal mucosal epithelial mitochondrial dehydrogenase activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoilium bromide. Ischemia-reperfusion increased intestinal mucosal apoptosis, NO(X) production in the portal vein, the amount of iNOS protein, and the release of cytochrome c, but not caspase-3. Inhibitors of iNOS significantly attenuated the induction of apoptosis, increased NO(X) production, and release of cytochrome c. Mitochondrial dysfunction was induced by ischemia-reperfusion, which was ameliorated by iNOS inhibitors. Our results indicate that iNOS is related to increased mucosal apoptosis in the rat small intestine after ischemia-reperfusion, which is partly explained by the release of cytochrome c from mitochondria to cytosols following mitochondrial dysfunction.

Animals↗

PubMed1983

The effects of verapamil on mitochondrial dysfunction associated with coronary reperfusion.

In order to clarify the protective mechanism of verapamil, the following experiment was performed. Twenty-four anesthetized dogs were divided into 3 groups of 8 animals each. In the first, the left anterior descending coronary artery (LAD) was occluded for 15 min; in the second, 5-min reperfusion was done following a 15-min occlusion; in the third, prior to 5-min reperfusion, verapamil (0.4 mg/kg) was infused for 5 min. In each group, heart mitochondria were prepared from the normal and occluded or reperfused areas and their functions were estimated polarographically. The contents of calcium, phospholipids and fatty acids in the mitochondria were also measured by atomic absorption spectrophotometry, Allen's method and gas chromatography, respectively. Although occlusion induced mitochondrial dysfunction, the dysfunction was exacerbated by reperfusion. Occlusion alone did not alter the contents of calcium, phospholipids and fatty acids in mitochondria, while occlusion and subsequent reperfusion increased calcium and fatty acids and decreased phospholipids in mitochondria. Verapamil prevented these reperfusion responses. These results suggest that reperfusion injury of mitochondria is based on the degradation of mitochondrial phospholipids, which is caused by an activation of phospholipase, being triggered by a calcium increase. Verapamil, a calcium antagonist, might protect against reperfusion injury by inhibiting the activation of phospholipase.

Animals↗

PubMed1999

Mitochondrial abnormalities in non-alcoholic steatohepatitis.

BACKGROUND/AIMS: We assessed mitochondrial morphology by electron microscopy and the prevalence of a mitochondrial gene deletion in patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease and non-fatty liver diseases. Respiratory chain function using a cytoplasmic hybrid (cybrid) assay was further studied in NASH patients and healthy controls. METHODS: Electron microscopy was performed in 26 specimens. Fifteen patients were studied by polymerase chain reaction to detect a 520-bp deletion product of the mitochondrial genome (dmtDNA). Cybrids were created by fusion of platelets with anaerobic neuroblastoma cells in six NASH patients and 12 controls. RESULTS: Eight of ten NASH, one of seven alcoholics and two of nine other patients had linear crystalline inclusions in megamitochondria (p<0.05). Three of five patients with alcohol-related liver disease had dmtDNA compared to one of five NASH patients and one of five non-steatohepatitis controls. Cybrid respiratory chain function in platelets was not different from that of controls. CONCLUSIONS: Respiratory chain dysfunction, if present in NASH, is not expressed in platelet-derived mitochondria. In contrast to alcohol-related liver disease with active drinking, NASH patients do not commonly express the 5-kb mitochondrial DNA gene deletion in liver tissue. As previously described in early alcohol-related liver disease, crystalline inclusions of unknown composition are seen in hepatic mitochondria in NASH. Their presence suggests either an adaptive process or mitochondrial injury.

Adult↗

PubMed1976

Morphometric studies on the rat liver in biliary obstruction.

The common bile ducts of the Wistar rats were ligated and severed, and liver biopsies were done weekly for 7 postoperative weeks. Light and electron microscopic specimens were prepared for the morphometric studies. The volume ratio of the hepatic parenchyma decline with the lapse of time after bile duct ligation. However, elevated mean sectional area of the nucleus, increased mitotic index and unchanged estimated weight of the hepatic parenchyma after biliary obstruction suggested that lost hepatocytes were compensated by regeneration. Mitochondrial swelling and curling of the cristae were noted in biliary obstruction in general. Moreover, both the number and volume ratio of the mitochondria were increased corresponding to the duration of biliary obstruction. These changes were interpreted as an adaptation process to mitochondrial dysfunction.

Animals↗

PubMed2001

A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion.

Evidence is presented showing that a neuronal isoform of nitric oxide synthase (NOS) is expressed in rat pancreatic islets and INS-1 cells. Sequencing of the coding region indicated a 99.8% homology with rat neuronal NOS (nNOS) with four mutations, three of them resulting in modifications of the amino acid sequence. Double-immunofluorescence studies demonstrated the presence of nNOS in insulin-secreting beta-cells. Electron microscopy studies showed that nNOS was mainly localized in insulin secretory granules and to a lesser extent in the mitochondria and the nucleus. We also studied the mechanism involved in the dysfunction of the beta-cell response to arginine and glucose after nNOS blockade with N(G)-nitro-L-arginine methyl ester. Our data show that miconazole, an inhibitor of nNOS cytochrome c reductase activity, either alone for the experiments with arginine or combined with sodium nitroprusside for glucose, is able to restore normal secretory patterns in response to the two secretagogues. Furthermore, these results were corroborated by the demonstration of a direct enzyme-substrate interaction between nNOS and cytochrome c, which is strongly reinforced in the presence of the NOS inhibitor. Thus, we provide immunochemical and pharmacological evidence that beta-cell nNOS exerts, like brain nNOS, two catalytic activities: a nitric oxide production and an NOS nonoxidating reductase activity, both of which are essential for normal beta-cell function. In conclusion, we suggest that an imbalance between these activities might be implicated in beta-cell dysregulation involved in certain pathological hyperinsulinic states.

Animals↗