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PubMed2002

Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool.

Microglial activation is common in several neurodegenerative disorders. In the present study, we used the murine BV-2 microglial cell line stimulated with gamma-interferon and lipopolysaccharide to gain new insights into the effects of endogenously produced NO on mitochondrial respiratory capacity, iron regulatory protein activity, and redox-active iron level. Using polarographic measurement of respiration of both intact and digitonin-permeabilized cells, and spectrophotometric determination of individual respiratory chain complex activity, we showed that in addition to the reversible inhibition of cytochrome-c oxidase, long-term endogenous NO production reduced complex-I and complex-II activities in an irreversible manner. As a consequence, the cellular ATP level was decreased in NO-producing cells, whereas ATPase activity was unaffected. We show that NO up-regulates RNA-binding of iron regulatory protein 1 in microglial cells, and strongly reduces the labile iron pool. Together these results point to a contribution of NO derived from inflammatory microglia to the misregulation of energy-producing reactions and iron metabolism, often associated with the pathogenesis of neurodegenerative disorders.

Aconitate Hydratase↗

PubMed2006

Homocysteine-induced endothelin-1 release is dependent on hyperglycaemia and reactive oxygen species production in bovine aortic endothelial cells.

BACKGROUND: Elevated plasma homocysteine (Hcy) is a risk factor for coronary disease. The objective of this study was to investigate whether Hcy either alone or in high glucose conditions induces endothelin-1 (ET-1) synthesis via the production of reactive oxygen species (ROS). METHODS: Bovine aortic endothelial cells were grown in high (25 mmol/l) and low (5 mmol/l) glucose medium. RESULTS: In high glucose, Hcy caused a time-dependent increase in ET-1 release, which was greatest with 50 micromol/l Hcy at 24 h (p < 0.01). This effect was not seen in low glucose conditions. In high glucose and 50 micromol/l Hcy, ET-1 mRNA levels were maximal after 1 h (p < 0.05). Tissue factor mRNA levels were raised at 4 h (p < 0.05) and functional activity was raised at 6 h (p < 0.01). Intracellular ROS production was increased by 50 micromol/l Hcy after 24 h (p < 0.05) but only in high glucose. To investigate the role of mitochondrial metabolism in ROS production, cells were incubated with thenoyltrifluoroacetone (inhibitor of complex II) or carbonyl cyanide m-chlorophenylhydrazone (uncoupler of oxidative phosphorylation). Both compounds abolished the Hcy-induced increase in ROS production and ET-1 release. There was an alteration in intracellular glutathione (GSH) levels with Hcy treatment with more oxidised GSH present. CONCLUSION: The combined metabolic burden of Hcy and high glucose stimulates ET-1 synthesis in bovine aortic endothelial cells via a mechanism dependent on the production of mitochondrial ROS, but may not be generalisable to all types of endothelial cells.

Animals↗

PubMed2002

Etiopathogenesis and clinical presentation of carotid body tumors.

The carotid body (CB) is a highly specialized small organ located at the bifurcation of the common carotid artery in the neck and plays an important role in acute adaptation to hypoxia. The most common diseased state of the carotid body is its enlargement (i.e., the CB paraganglioma), which can be caused by a genetic predisposition (hereditary paraganglioma, PGL) and by chronic hypoxic stimulation. The CB is the most common tumor site in head and neck paragangliomas. Currently, inactivating germline mutations in the mitochondrial complex II subunits SDHB, SDHC, and SDHD have been identified as genetic risk factors for CB tumors (CBTs). Another locus at chromosome 11q13, identified by linkage analysis in a single family, may harbor a fourth susceptibility gene. Although CBTs are mostly slow-growing and benign, they can cause significant morbidity because of their proximity to major arteries and nerves in the head and neck. Here, we review the etiological factors implicated in the development of CBTs and provide information pertaining to their clinical presentation. Although CBTs are rare, they have the potential to provide unique insights for tumorigenesis and oxygen sensing and signaling mechanisms.

Carotid Body Tumor↗

PubMed1996

Genes encoding the same three subunits of respiratory complex II are present in the mitochondrial DNA of two phylogenetically distant eukaryotes.

Although mitochondrial DNA is known to encode a limited number (<20) of the polypeptide components of respiratory complexes I, III, IV, and V, genes for components of complex II [succinate dehydrogenase (ubiquinone); succinate:ubiquinone oxidoreductase, EC 1.3.5.1] are conspicuously lacking in mitochondrial genomes so far characterized. Here we show that the same three subunits of complex II are encoded in the mitochondrial DNA of two phylogenetically distant eukaryotes, Porphyra purpurea (a photosynthetic red alga) and Reclinomonas americana (a heterotrophic zooflagellate). These complex II genes, sdh2, sdh3, and sdh4, are homologs, respectively, of Escherichia coli sdhB, sdhC, and sdhD. In E. coli, sdhB encodes the iron-sulfur subunit of succinate dehydrogenase (SDH), whereas sdhC and sdhD specify, respectively, apocytochrome b558 and a hydrophobic 13-kDa polypeptide, which together anchor SDH to the inner mitochondrial membrane. Amino acid sequence similarities indicate that sdh2, sdh3, and sdh4 were originally encoded in the protomitochondrial genome and have subsequently been transferred to the nuclear genome in most eukaryotes. The data presented here are consistent with the view that mitochondria constitute a monophyletic lineage.

Amino Acid Sequence↗

PubMed1999

Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase.

We have mapped large (cybL) and small (cybS) subunits of cytochrome b in the succinate-ubiquinone oxidoreductase (complex II) of human mitochondria to chromosome 1q21 and 11q23, respectively (H. Hirawake et al., Cytogenet. Cell Genet. 79 (1997) 132-138). In the present study, the human SDHD gene encoding cybS was cloned and characterized. The gene comprises four exons and three introns extending over 19 kb. Sequence analysis of the 5' promoter region showed several motifs for the binding of transcription factors including nuclear respiratory factors NRF-1 and NRF-2 at positions -137 and -104, respectively. In addition to this gene, six pseudogenes of cybS were isolated and mapped on the chromosome.

Amino Acid Sequence↗

PubMedDate not supplied

Chronic stavudine exposure induces hepatic mitochondrial toxicity in adult Erythrocebus patas monkeys.

OBJECTIVES: To understand the mitochondrial mechanisms underlying the lactic acidosis and hepatic steatosis seen in some HIV-1-infected individuals after long-term stavudine (d4T) exposure, we have explored mitochondrial integrity in adult monkeys (Erythrocebus patas) given a daily human equivalent dose of d4T for 78 days. STUDY DESIGN/METHODS: Three Erythrocebus patas (patas) monkeys were given 3 mg d4T orally twice daily (total 6 mg d4T), or approximately 1.2 mg d4T/kg body weight per day, for 78 days and compared with 3 unexposed animals. Blood taken from controls and from treated monkeys before and after drug exposure was subjected to a complete clinical chemistry profile. Liver and skeletal muscles were examined for oxidative phosphorylation enzyme specific activities, mitochondrial deoxyribonucleic acid (mtDNA) quantity by slot blot, and mtDNA integrity by Southern blot. RESULTS: Clinical chemistry assays demonstrated few significant differences; however, one d4T-exposed monkey had a serum lactate of 8.1 mmol/L after 78 days of oral d4T ingestion. Specific activities of oxidative phosphorylation Complexes I, II, and IV were significantly altered in both livers and skeletal muscles from the d4T-exposed animals, compared with the controls (p < or = 0.05). Significant depletion of mitochondrial DNA was observed in livers of drug-exposed monkeys, but not in skeletal muscle (p < or = 0.05). Further examination of liver DNA by Southern blot confirmed hepatic mtDNA depletion in drug exposed animals. CONCLUSIONS: The data suggest that direct examination of the liver may be required to elucidate clinical d4T-induced hepatotoxicity related to mitochondrial damage.

Animals↗

PubMed2002

Archaeal complex II: 'classical' and 'non-classical' succinate:quinone reductases with unusual features.

Reversible succinate dehydrogenase (SDH) activities have been ubiquitously detected in organisms from the three domains of life. They represent constituents either of respiratory complexes II in aerobes, or of fumarate dehydrogenase complexes in anaerobes. The present review gives a survey on archaeal succinate:quinone oxidoreductases (SQRs) analyzed so far. Though some of these could be studied in detail enzymologically and spectroscopically, the existence of others has been deduced only from published genome sequences. Interestingly, two groups of enzyme complexes can be distinguished in Archaea. One group resembles the properties of SDHs known from bacteria and mitochondria. The other represents a novel class with an unusual iron-sulfur cluster in subunit B and atypical sequence motifs in subunit C which may influence electron transport mechanisms and pathways. This novel class of SQRs is discussed in comparison to the so-called 'classical' complexes. A phylogenetic analysis is presented suggesting a co-evolution of the flavoprotein-binding subunit A and subunit B containing the three iron-sulfur clusters.

Amino Acid Sequence↗

PubMed2006

Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders.

Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the beta-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders.

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

PubMed2001

Acidianus ambivalens Complex II typifies a novel family of succinate dehydrogenases.

Complex II from the thermoacidophilic archaeon Acidianus ambivalens, an archetype of an emerging class of succinate dehydrogenases (SDH), was extracted from intact membranes and purified to homogeneity. The complex contains one molecule of covalently bound FAD and 10 Fe atoms. EPR studies showed that the complex contains the canonical centres S1 ([2Fe-2S]2+/1+) and S2 ([4Fe-4S]+2/+1) but lacks centre S3 ([3Fe-4S]+1/0); these observations agree with the fact that the iron-sulfur subunit contains an extra cysteine that may allow the binding of a new centre, most probably a tetranuclear one. Succinate-driven oxygen consumption is observed in intact membranes indicating that in vivo, complex II operates as a succinate:quinone oxidoreductase, despite missing the typical anchor domain subunits. The pure complex was found to contain bound caldariella quinone, the enzyme physiological partner. An alternative membrane anchoring for this new type of SDHs, based on the amphipathic nature of the putative helices found in SdhC, is suggested.

Amino Acid Sequence↗

PubMed2001

Depletion of glutathione up-regulates mitochondrial complex I expression in glial cells.

Glutathione deficiency is commonly associated with mitochondrial complex I dysfunction and loss of viability in neurones, but not in glia. In order to address the possible mechanism responsible for this cellular difference, the regulation of mitochondrial complex I expression by glutathione depletion was investigated in glial cells. Incubation of rat-cultured astrocytes and C6 glioma cells with the specific gamma-glutamylcysteine synthetase inhibitor L-buthionine-(S:,R:)-sulfoximine (L-BSO; 0.1-1 mM) decreased the total specific content of glutathione in a dose- and time-dependent fashion. Northern blot analyses revealed that glutathione deficiency caused by L-BSO (0.1 mM) was associated with a twofold enhancement in complex I regulatory subunit ND6 (mitochondrially encoded) mRNA expression after 24-72 h. This effect was accompanied by a twofold increase in complex-I activity at 72 h in L-BSO-treated cells, as compared with control cells, but complex II-III, complex IV and citrate synthase activities were unaltered. It is suggested that the oxidative stress caused by glutathione depletion in glial cells would up-regulate complex-I activity by enhancing the expression of the mitochondrially encoded regulatory subunit. These results could offer further insight into the different degree of cellular susceptibility observed in glial vs. neuronal cells against oxidative stress.

Animals↗

PubMed2002

The four subunits of mitochondrial respiratory complex II are encoded by multiple nuclear genes and targeted to mitochondria in Arabidopsis thaliana.

Mitochondrial respiratory complex II contains four subunits: a flavoprotein (SDHI), an iron-sulphur subunit (SDH2) and two membrane anchor subunits (SDH3 and SDH4). We have found that in Arabidopsis thaliana SDH I and SDH3 are encoded by two, and SDH4 by one nuclear genes, respectively. All these encoded polypeptides are found to be imported into isolated plant mitochondria. While both SDHI proteins are highly conserved when compared to their counterparts in other organisms, SDH3 and SDH4 share little similarity with non-plant homologues. Expression of SDH1-1, SDH3 and SDH4 genes was detected in all tissues analysed, with the highest steady-state mRNA levels found in flowers and inflorescences. In contrast, the second SDH1 gene (SDH1-2) is expressed at a low level.

Amino Acid Sequence↗

PubMed1994

Interactions between ubiquinones and vitamins in membranes and cells.

The interaction between ubiquinones and vitamin E was studied in the inner membranes of rat liver mitochondria, liposomes and human erythrocyte plasma membranes. Free radicals were produced by addition of exogenous oxidants, and their reaction with chromanols and ubiquinone was followed by ESR and HPLC. Membranes were made deficient in ubiquinone but sufficient in alpha-tocopherol and were reconstituted with added ubiquinone. With these membrane preparations it was shown that (i) in the inner mitochondrial membranes there is a requirements for ubiquinone in the enzymatic recycling of vitamin E; (ii) succinate-ubiquinone reductase incorporated in liposomes cannot protect vitamin E in the absence of ubiquinone and (iii) in human erythrocyte plasma membranes protection against the loss of vitamin E can be provided by NADH-cytochrome-b5-dependent enzymatic recycling. We conclude that ubiquinonols (ubisemiquinones) reduce vitamin E through electron transport.

Animals↗

PubMed1995

Deficiencies of NADH and succinate dehydrogenases in degenerative diseases and myopathies.

This paper examines the experimental foundations of reports in the literature on mitochondrial diseases involving Complexes I and II of the respiratory chain. Many of the reports may be questioned on the basis of the assay conditions used which disregard established knowledge of the precautions required for valid activity measurements. In addition, some findings are open to question because of the experimental material chosen for the study, such as the measurement of NADH oxidase activity in platelets in Parkinson's disease, which affects selectively the dopamine neurons, or the use of autopsy material stored for prolonged periods during which post-mortem changes may have occurred. Deficiencies claimed to involve several components of the respiratory chain may reflect indirect effects, such as defects in the synthesis of iron-sulfur clusters or in the availability of iron, rather than mutations in the genes coding for the deficient enzymes. Nevertheless, there are a few instances reported of Complex II deficiency free from such criticisms. As to Complex I, idiopathic Parkinsonism appears to involve a documentable decline in the activity of this enzyme. Using the model system provided by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces biochemical, pharmacological, and clinical syndromes closely resembling Parkinsonism, the etiology of the disease is examined.

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

PubMed1986

Affinity labelling of Escherichia coli ribosomes with a benzylidene derivative of AUGU6 within initiation and pretranslocational complexes.

Affinity labelling of E. coli ribosomes with the 2',3'-O-[4-(N-2-chloroethyl)-N-methylamino]benzylidene derivative of AUGU6 was studied within the initiation complex (complex I) obtained by using fMet-tRNAMetf and initiation factors and within the pretranslocational complex (complex II) obtained by treatment of complex I with the ternary complex Phe-tRNAPhe.GTP.EF-Tu. Both proteins and rRNA of 30 S as well as 50 S subunits were found to be labelled. Sets of proteins labelled within complexes I and II differ considerably. Within complex II, proteins S13 and L10 were labelled preferentially. On the other hand, within complex I, multiple modification is observed (proteins S4, S12, S13, S14, S15, S18, S19, S20/L26 were found to be alkylated) despite the single fixation of a template in the ribosome by interaction of the AUG codon with fMet-tRNAMetf.

Affinity Labels↗

PubMed2005

Crystallization of mitochondrial respiratory complex II from chicken heart: a membrane-protein complex diffracting to 2.0 A.

A procedure is presented for preparation of diffraction-quality crystals of a vertebrate mitochondrial respiratory complex II. The crystals have the potential to diffract to at least 2.0 A with optimization of post-crystal-growth treatment and cryoprotection. This should allow determination of the structure of this important and medically relevant membrane-protein complex at near-atomic resolution and provide great detail of the mode of binding of substrates and inhibitors at the two substrate-binding sites.

Animals↗

PubMed2003

Effects of thyroid state on H2O2 production by rat heart mitochondria: sites of production with complex I- and complex II-linked substrates.

This work was designed to determine possible effects of altered thyroid states on rates and sites of H 2 O 2 production by rat heart mitochondria. Rates of O 2 consumption and H 2 O 2 release, capacities to remove the peroxide, lipid peroxidation, cytochrome oxidase activities and ubiquinone levels were determined in heart mitochondria from euthyroid, hypothyroid, and hyperthyroid rats. Hypothyroidism decreased, whereas hyperthyroidism increased the rates of O 2 consumption and H 2 O 2 release during both state 4 and state 3 respiration with Complex I- or Complex II-linked substrates. The percentage of O 2 released as H 2 O 2 was not significantly affected by thyroid state. However, the mitochondrial capacity to remove H 2 O 2 increased in the transition from hypothyroid to hyperthyroid state, which indicates that H 2 O 2 production did not modify in proportion to the rate of O 2 consumption. The thyroid-state-linked changes in H 2 O 2 production were well correlated with the levels of hydroperoxides. Rates of H 2 O 2 release in the presence of respiratory inhibitors indicated that changes in the H 2 O 2 production occurred at both sites at which H 2 O 2 was generated in euthyroid state. This result and the observation that ubiquinol levels and cytochrome oxidase activities increase in the transition from hypothyroid to hyperthyroid state suggest that the modifications of H 2 O 2 production are due to a modulation by thyroid hormone of mitochondrial content of autoxidisable electron carriers.

Animals↗

PubMed2006

Mitochondrial regulation of hypoxia-induced increase of adrenomedullin mRNA in HL-1 cells.

Hypoxia upregulates the expression of the cardioprotective peptide adrenomedullin in cardiomyocytes. We characterized this pathway in murine HL-1 cardiomyocytes. Inhibition of mitochondrial complexes I, III, and IV largely, but not completely, reduced hypoxic adrenomedullin mRNA increase in gas-impermeable culture plates. Complex III inhibition was also effective in permeable culture plates, so that this effect is unlikely due to intracellular oxygen redistribution, whereas complex I blockade was ineffective in permeable plates. Complex II does not participate in this effect, as shown by chemical and siRNA inactivation. ROS scavenging by nitroblue tetrazolium and general flavoprotein inhibition by diphenyleniodonium nearly abrogated the hypoxic adrenomedullin mRNA increase. Thus, ROS production by flavoproteins is crucial for hypoxic upregulation of adrenomedullin mRNA in murine HL-1 cardiomyocytes. These ROS originate both from the mitochondrial complex III and from additional, presumably extramitochondrial, sources. Mitochondrial oxygen consumption appears to have impact on oxygen availability at these extramitochondrial sensors.

Adrenomedullin↗

PubMed2003

Hyperglycemia increases mitochondrial superoxide in retina and retinal cells.

Oxidative stress is believed to play a significant role in the development of diabetic retinopathy. In this study, we have investigated the effects of elevated glucose concentration on the production of superoxide anion by retina and retinal cells, the cellular source of the superoxide, the effect of therapies that are known to inhibit diabetic retinopathy on the superoxide production, and the role of the superoxide in cell death in elevated glucose concentration. Superoxide release was measured from retinas collected from streptozotocin-diabetic rats (2 months) treated with or without aminoguanidine, aspirin, or vitamin E, and from transformed retinal Müller cells (rMC-1) and bovine retinal endothelial cells (BREC) incubated in normal (5 mM) and high (25 mM) glucose. Diabetes (retina) or incubation in elevated glucose concentration (rMC-1 and BREC cells) significantly increased superoxide production, primarily from mitochondria, because an inhibitor of mitochondrial electron transport chain complex II normalized superoxide production. Inhibition of reduced nicotinamine adenine dinucleotide phosphate (NADPH) oxidase or nitric oxide synthase had little or no effect on the glucose-induced increase in superoxide. Treatment of diabetic animals with aminoguanidine, aspirin, or vitamin E for 2 months significantly inhibited the diabetes-induced increase in production of superoxide in the retinas. Despite the increased production of superoxide, no increase in protein carbonyls was detected in retinal proteins from animals diabetic for 2-6 months or rMC-1 cells incubated in 25 mM glucose for 5 d unless the activities of calpain or the proteosome were inhibited. Addition of copper/zinc-containing superoxide dismutase to the media of rMC-1 and BREC cells inhibited the apoptotic death caused by elevated glucose. Diabetes-like glucose concentration increases superoxide production in retinal cells, and the superoxide contributes to impaired viability and increased cell death under those circumstances. Three therapies that inhibit the development of diabetic retinopathy all inhibit superoxide production, raising a possibility that these therapies inhibit retinopathy in part by inhibiting a hyperglycemia-induced increase in superoxide production.

Actins↗