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PubMed2003

A study of metabolic compartmentation in the rat heart and cardiac mitochondria using high-resolution magic angle spinning 1H NMR spectroscopy.

High-resolution magic angle spinning (MAS) (1)H nuclear magnetic resonance (NMR) spectroscopy is increasingly being used to monitor metabolic abnormalities within cells and intact tissues. Many toxicological insults and metabolic diseases affect subcellular organelles, particularly mitochondria. In this study high-resolution (1)H NMR spectroscopy was used to examine metabolic compartmentation between the cytosol and mitochondria in the rat heart to investigate whether biomarkers of mitochondrial dysfunction could be identified and further define the mitochondrial environment. High-resolution MAS spectra of mitochondria revealed NMR signals from lactate, alanine, taurine, choline, phosphocholine, creatine, glycine and lipids. However, spectra from mitochondrial extracts contained additional well-resolved resonances from valine, methionine, glutamine, acetoacetate, succinate, and aspartate, suggesting that a number of metabolites bound within the mitochondrial membranes occur in 'NMR invisible' environments. This effect was further investigated using diffusion-weighted measurements of water and NMR spectroscopy during state 2 and state 3 respiration. State 3 respiration caused a decrease in the resonance intensity of endogenous succinate compared with state 2 respiration, suggesting that coupled respiration may also modulate the NMR detection of metabolites within mitochondria.

Amino Acids↗

PubMed1987

Variation in the levels of complex I subunits among tissues in a patient with mitochondrial encephalomyopathy and renal dysfunction.

Enzymic activity and the levels of immunochemically detectable subunits of NADH-ubiquinone oxidoreductase (Complex I) were measured in the mitochondria from various tissues of a patient with mitochondrial encephalomyopathy and renal dysfunction. Rotenone-sensitive NADH-cytochrome c reductase activity was decreased in all the tissues examined, but the degree of deficiency varied from tissue to tissue. The levels of subunits in Complex I were decreased roughly in parallel with the activity in each tissue. These results indicate that the apparently tissue-specific manifestation of symptoms depends mainly on the levels of subunits in Complex I.

Adolescent↗

PubMed2006

Mitochondria in Parkinson disease: back in fashion with a little help from genetics.

Parkinson disease is a devastating neurodegenerative disorder with no known cure. Impairment in mitochondrial dysfunction is thought to play a major role in the pathogenesis. Recent genetic advances suggest that mitochondrial dysfunction may be the primary defect. Drugs that target the mitochondria may therefore represent the best hope for disease-modifying therapies in Parkinson disease.

Humans↗

PubMed2000

Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy.

Mitochondria are cellular organelles crucial for energy supply and calcium homeostasis in neuronal cells, and their dysfunction causes seizure activity in some rare human epilepsies. To directly test whether mitochondrial respiratory chain enzymes are abnormal in the most common form of chronic epilepsy, temporal lobe epilepsy (TLE), living human brain specimens from 57 epileptic patients and 2 nonepileptic controls were investigated. In TLE patients with a hippocampal epileptic focus, we demonstrated a specific deficiency of complex I of the mitochondrial respiratory chain in the hippocampal CA3 region. In contrast, TLE patients with a parahippocampal epileptic focus showed reduced complex I activity only in parahippocampal tissue. Inhibitor titrations of the maximal respiration rate of intact human brain slices revealed that the observed reduction in complex I activity is sufficient to affect the adenosine triphosphate production rate. The abnormal complex I activity in the hippocampal CA3 region was paralleled by increased succinate dehydrogenase staining of neurons and marked ultrastructural abnormalities of mitochondria. Therefore, mitochondrial dysfunction is suggested to be specific for the epileptic focus and may constitute a pathomechanism contributing to altered excitability and selective neuronal vulnerability in TLE.

Adolescent↗

PubMedDate not supplied

Doxorubicin-derived metabolites induce release of cytochrome C and inhibition of respiration on cardiac isolated mitochondria.

BACKGROUND: The generation of doxorubicin metabolites other than semiquinone free radicals and mitochondrial dysfunction have been implicated in doxorubicin (DOX)-induced cardiotoxicity. This study examines pro-apoptotic mechanisms in isolated rat cardiac mitochondria exposed to DOX-derived cardiac metabolites i.e. doxorubicinol, doxorubicin aglycone and doxorubicinol aglycone. MATERIALS AND METHODS: Freshly isolated mitochondria were incubated in the presence of doxorubicin and its derivatives and the released cytochrome c was detected by Western blotting analysis. Oxygen consumption was measured with a Clark-type oxygen electrode and mitochondrial transmembrane potential (delta psi) was measured in a fluorometer in the presence of a fluorescent probe. RESULTS: The data obtained show that exposure of isolated mitochondria to the drugs determines a significant release of cytochrome c and a slight decrease in the mitochondrial transmembrane potential (delta psi). These effects are more evident when the experiments are performed in the presence of the aglycone derivatives. Moreover, an inhibition of the respiratory chain at the level of complex I is evidenced in the drug-treated mitochondria. CONCLUSION: The data obtained are consistent with the proposal that doxorubicin-induced cardiotoxicity may be partially exerted by the induction of programmed cell death, both directly and even more through its derived metabolites.

Animals↗

PubMed2005

Mitochondria take center stage in aging and neurodegeneration.

A critical role of mitochondrial dysfunction and oxidative damage has been hypothesized in both aging and neurodegenerative diseases. Much of the evidence has been correlative, but recent evidence has shown that the accumulation of mitochondrial DNA mutations accelerates normal aging, leads to oxidative damage to nuclear DNA, and impairs gene transcription. Furthermore, overexpression of the antioxidant enzyme catalase in mitochondria increases murine life span. There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage in these diseases therefore have great promise.

Aging↗

PubMed2000

Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis.

Glutamate toxicity on PC12 cells is mediated by oxidative stress as a consequence of the inhibition of a cystine uptake system with depletion of GSH. In this study we report that glutamate decreases PC12 cell viability, inhibiting the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). This decrease was prevented by the antioxidants vitamin E, idebenone and L-deprenyl, which were also shown to be effective in reducing the accumulation of reactive oxygen species (ROS) in cells exposed to glutamate, decreasing the fluorescence of 2',7'-dichlorofluorescein (DCF). Incubation of PC12 cells with high glutamate concentrations induced mitochondrial dysfunction, leading to the loss of mitochondrial transmembrane potential, evaluated as a decrease in rhodamine 123 (Rh123) retention by mitochondria, and to the decrease of intracellular ATP levels. The mitochondrial dysfunction, induced by glutamate, can be involved in the observed increase of [Ca2+]i. The elevation of [Ca2+]i occurred after GSH depletion, suggesting that oxidative stress is involved in the disturbances of intracellular calcium homeostasis. In conclusion, our data indicate that glutamate, at concentrations which block cystine uptake in PC12 cells leading to GSH depletion and inducing oxidative stress, increases ROS accumulation and decreases cell survival by a mechanism involving mitochondrial dysfunction and impairment of Ca2+ homeostasis.

Animals↗

PubMed2000

Skeletal muscle ultrastructure in normal pregnancy and preeclampsia.

The aim of this study was to assess by quantitative methods whether the assumed metabolic disturbance underlying preeclampsia would be reflected in muscle cell composition of lipid, mitochondria, or glycogen. We have reported mitochondrial dysfunction in preeclampsia, and since accumulation of lipid in skeletal muscle is a feature in mitochondrial disorders, our hypothesis was that preeclamptic women would have an increased content of triglyceride droplets. Quantitative investigation of the skeletal muscle ultrastructure was performed in 10 women with severe preeclampsia and in 6 normotensive pregnant women. Biopsy specimens from musculus rectus abdominis were taken during cesarean section and prepared for electron microscopy. Random pictures were taken by transmission electron microscopy, and point-counting stereology was performed. Preeclamptic women did not have a higher lipid volume fraction than normotensive pregnant women, and we had to reject our hypothesis. On the contrary, there was a tendency towards a lower triglyceride volume fraction in pre eclampsia. We did not detect differences in relative volumes of mitochondria or glycogen in skeletal muscle between the two groups.

Adolescent↗

PubMed1999

Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease.

Both reactive dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson's disease. Dopamine metabolites, dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether dopamine oxidation products alter mitochondrial function. We found that exposure to dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to dopamine quinone formation. In contrast, dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson's disease and methamphetamine-induced neurotoxicity.

Animals↗

PubMed1998

Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A.

The purpose of this study was to test the hypothesis that mitochondrial permeability transition might be implicated in mitochondrial and intact organ dysfunctions associated with damage induced by reperfusion after cold ischaemia. Energetic metabolism was assessed continuously by 31P-NMR on a model system of isolated perfused rat liver; mitochondria were extracted from the livers and studied by using top-down control analysis. During the temperature transition from hypothermic to normothermic perfusion (from 4 to 37 degrees C) the ATP content of the perfused organ fell rapidly, and top-down metabolic control analysis of damaged mitochondria revealed a specific control pattern characterized by a dysfunction of the phosphorylation subsystem leading to a decreased response to cellular ATP demand. Both dysfunctions were fully prevented by cyclosporin A, a specific inhibitor of the mitochondrial transition pore (MTP). These results strongly suggest the involvement of the opening of MTP in vivo during the transition to normothermia on rat liver mitochondrial function and organ energetics.

Animals↗

PubMed2005

Rtg2 protein: at the nexus of yeast longevity and aging.

Firm support for the notion that metabolism and particularly mitochondrial metabolism plays a significant role in aging has been gathered in studies on yeast. As in other organisms, mitochondria contribute to aging through their propensity to generate reactive oxygen species. There is more to the involvement of mitochondria in aging than this, however. Mitochondrial dysfunction, which accumulates during aging, triggers the retrograde response, an intracellular signaling pathway that activates genes that compensate for this dysfunction. A key signaling protein in this pathway is the Rtg2 protein. Recent studies have provided evidence that this protein lies at the nexus of the four major processes that are involved in aging in yeast and in other organisms; namely, metabolism, stress resistance, chromatin-dependent gene regulation, and genome stability. The details of this central role of Rtg2 protein explain the delicate balance between longevity and aging, which ultimately must tip towards the latter. Phenomena that resemble the retrograde response appear to exist in human cells, with both common and cell type-specific gene expression changes as the output.

Adaptation, Physiological↗

PubMed2005

Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke.

Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate ATP through oxidative phosphorylation via the electron transport chain. Reactive oxygen radicals generated from mitochondria have been implicated in acute brain injuries, like stroke and neurodegeneration. Recent studies have shown that mitochondrially formed oxidants are mediators of molecular signaling and have implicated mitochondria-dependent apoptosis involving pro- and antiapoptotic protein binding, the release of cytochrome c and Smac, the activation of downstream caspase-9 and -3, and the fragmentation of DNA. Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3-kinase (PI3-K)/Akt and downstream signaling molecular bindings like Bad/Bcl-X(L) and phosphorylated Bad/14-3-3. Genetically modified mice (SOD1, SOD2) or rats that overexpress or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.

Animals↗

PubMed1987

Inhibited efficiency of kidney mitochondria isolated from rats treated with cyclosporin A.

The effect of cyclosporin A (CYA) on the respiration and phosphorylation in rat kidney mitochondria was studied. When CYA (50 mg/kg/day) was subcutaneously administered to rats for 4 days, the state 3 respiration and uncoupled respiration of succinate and glutamate/malate respiration was decreased. The respiratory control index was decreased in glutamate/malate respiration. These ex vivo effects of mitochondrial dysfunction are discussed as CYA effects on kidney mitochondria occurring in the intact cell. The nephrotoxic effect of CYA could be demonstrated by increased excretions of urinary enzymes.

Animals↗

PubMed2002

Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy.

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.

Adrenergic beta-Antagonists↗

PubMed1999

Repopulation of rho0 cells with mitochondria from a patient with a mitochondrial DNA point mutation in tRNA(Gly) results in respiratory chain dysfunction.

Familial hypertrophic ventricular cardiomyopathy has been demonstrated to be associated with a number of mitochondrial DNA (mtDNA) mutations. A fibroblast cell line carrying a mutation in its mtDNA at position 9997 in the gene encoding tRNA glycine was obtained from a patient with hypertrophic cardiomyopathy. To demonstrate that the etiology of this disease was a result of the mtDNA mutation, cybrid clones were constructed by fusion of enucleated patient skin fibroblasts to rho0 osteosarcoma cells. Clones carrying high levels of mutant mtDNA showed predominantly cytochrome c oxidase and complex I deficiency, as well as an elevated lactate/pyruvate (L/P) ratio, a biochemical marker characteristic of respiratory chain deficiencies. Pulse-labeling experiments demonstrated a strong negative correlation between the levels of newly synthesized mtDNA-encoded polypeptides and glycine content. These data suggest that the T9997C mutation in mtDNA is causative of respiratory chain dysfunction when present at high levels of heteroplasmy.

Blotting, Southern↗

PubMed2002

Understanding the impact of mitochondrial defects in cardiovascular disease: a review.

OBJECTIVE: Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophic cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, and myocarditis. A genetic basis has been established for some mitochondrial abnormalities (eg, mitochondrial DNA changes leading to oxidative phosphorylation dysfunction, fatty acid beta-oxidation (FAO) defects resulting from specific nuclear mutations) whereas other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized. METHODS: This article reviews mitochondrial abnormalities in structure or function reported in cardiac diseases highlighting information about their potential etiology, significance in cardiac pathogenesis, and diagnostic and therapeutic options available to the clinician. We also provide a brief background concerning mitochondrial biogenesis and bioenergetic pathways in cardiac growth, development, and aging. CONCLUSIONS: Although aberrations in bioenergetic functioning of mitochondria appear to be most often related to cardiac dysfunction, the primary defect(s) causing bioenergetic dysfunction may reside in a nonbioenergetic pathway (eg, signaling between mitochondria and nucleus) or in overall mitochondrial biogenesis or degradation pathways.

Aging↗

PubMed2005

Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: role of mitochondrial permeability transition.

Liver cirrhosis is often preceded by overt signs of hepatitis, including parenchymal cell inflammation and infiltration of polymorphonuclear (PMN) leukocytes. Activated PMNs release both reactive oxygen species and reactive halogen species, including hypochlorous acid (HOCl), which are known to be significantly cytotoxic due to their oxidizing potential. Because the role of mitochondria in the hepatotoxicity attributed to HOCl has not been elucidated, we investigated the effects of HOCl on mitochondrial function in the human hepatoma HepG2 cell line, human fetal liver cells, and isolated rat liver mitochondria. We show here that HOCl induced mitochondrial dysfunction, and apoptosis was dependent on the induction of the mitochondrial permeability transition (MPT), because HOCl induced mitochondrial swelling and collapse of the mitochondrial membrane potential with the concomitant release of cytochrome c. These biochemical events were inhibited by the classical MPT inhibitor cyclosporin A (CSA). Cell death induced by HOCl exhibited several classical hallmarks of apoptosis, including annexin V labeling, caspase activation, chromatin condensation, and cell body shrinkage. The induction of apoptosis by HOCl was further supported by the finding that CSA and caspase inhibitors prevented cell death. For the first time, these results show that HOCl activates the MPT, which leads to the induction of apoptosis and provides a novel insight into the mechanisms of HOCl-mediated cell death at sites of chronic inflammation.

Animals↗

PubMed2005

Retrograde regulation due to mitochondrial dysfunction may be an important mechanism for carcinogenesis.

Mitochondrial dysfunction has crucial importance in carcinogenesis. Due to several reasons, it may lead to insufficiency in the electron transport chain, which activates a series of cytosolic proteins. These proteins are transported to the nucleus and promote the activation of genes leading to intracellular diverse metabolic, regulatory, signalization and stress-related pathways. Retrograde regulation is the general term for mitochondrial signaling, and is broadly defined as cellular responses to alterations in functional state of mitochondria. This signaling pathway is triggered by mitochondrial dysfunction. The retrograde response is not a simple On-Off switch, but rather it responds in a continuous manner to the changing metabolic needs of the cell. Communication between mitochondria and the nucleus is important for a variety of cellular processes such as carbohydrate and nitrogen metabolism, cell cycle and proliferation, and cell growth and morphogenesis. As a result of retrograde regulation, the cell, actually a component of the multicellular organism, transforms to a unicellular lifestyle and initiates a developing course, independent of the systemic structure. This transformed cell runs metabolic regulations effectively in order to utilize all energy depots, mainly the adipose tissue of the multicellular organism. The most important one is the active utilization of glyoxylate cycle, through which the malign cells supply glucose from fats. Continuously acting glycolysis and gluconeogenesis, fatty acid oxidation and de novo lipogenesis constitute futile cycles. This in turn causes cachexia by maintaining the organism in constant negative energy balance. Mitochondria-to-nucleus stress signaling activates some of the genes implicated in tumor progression and tumor cell metastasis. Retrograde regulation also renders the cell more resistant to apoptosis. It is becoming clearer which genes control the retrograde response in human cells. Most probably, MYC is one of the transcription factors necessary for this response.

Cell Transformation, Neoplastic↗