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PubMed2001

Association between seminal plasma carnitine and sperm mitochondrial enzymatic activities.

Cellular parameters of the seminogram have been previously shown to correlate with L-carnitine concentration in the seminal fluid. Carnitine is involved in a variety of metabolic processes playing an important role in maintaining an active oxidative phosphorylation (OXPHOS). Recently, we have found a significant association between the specific activities of the respiratory chain complexes and the seminogram parameters and here we have studied the relationship between the spermatozoa OXPHOS activities and L-carnitine concentration in the seminal plasma. Carnitine, but not prostatic secretions, positive and significantly correlate with mitochondrial respiratory complex activities and the citric acid cycle enzymes citrate synthase and succinate dehydrogenase. It is remarkable that the ratios of the respiratory chain complexes to citrate synthase or succinate dehydrogenase, significant but negatively correlated with L-carnitine concentration. As carnitine in seminal plasma is secreted from the epididymis our results strongly suggest that relationships between carnitine secretion, seminal quality and OXPHOS activities could be because of a parallel response to the same regulatory event.

Carnitine↗
PubMed2001

Metabolic testing in mitochondrial disease.

Mitochondrial oxidative phosphorylation (OXPHOS) disorders are a heterogeneous group of diseases with variable expression that often pose diagnostic dilemmas. Although definitive diagnosis of these disorders usually requires a muscle biopsy and mtDNA and enzymatic testing, standard metabolic studies including organic acid and amino acid analysis often provide useful findings that support an OXPHOS disease and the need for more invasive studies. In addition, the detection of possible metabolic derangements, such as elevated lactate levels, may lead to improved long-term outcomes for affected patients through the use of various treatment regimens. Similarly, long-term yearly monitoring of diagnosed OXPHOS patients with metabolic testing is also warranted.

Education, Medical, Continuing↗
PubMed1999

Mitochondrial disease in mouse results in increased oxidative stress.

It has been hypothesized that a major factor in the progression of mitochondrial disease resulting from defects in oxidative phosphorylation (OXPHOS) is the stimulation of the mitochondrial production of reactive oxygen species (ROS) and the resulting damage to the mtDNA. To test this hypothesis, we examined the mitochondria from mice lacking the heart/muscle isoform of the adenine nucleotide translocator (Ant1), designated Ant1(tm2Mgr) (-/-) mice. The absence of Ant1 blocks the exchange of ADP and ATP across the mitochondrial inner membrane, thus inhibiting OXPHOS. Consistent with Ant1 expression, mitochondria isolated from skeletal muscle, heart, and brain of the Ant1-deficient mice produced markedly increased amounts of the ROS hydrogen peroxide, whereas liver mitochondria, which express a different Ant isoform, produced normally low levels of hydrogen peroxide. The increased production of ROS by the skeletal muscle and heart was associated with a dramatic increase in the ROS detoxification enzyme manganese superoxide dismutase (Sod2, also known as MnSod) in muscle tissue and muscle mitochondria, a modest increase in Sod2 in heart tissue, and no increase in heart mitochondria. The level of glutathione peroxidase-1 (Gpx1), a second ROS detoxifying enzyme, was increased moderately in the mitochondria of both tissues. Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the Ant1-deficient mice showed a striking increase in the accumulation of mtDNA rearrangements, whereas skeletal muscle, with higher antioxidant defenses, had fewer mtDNA rearrangements. Hence, inhibition of OXPHOS does increase mitochondrial ROS production, eliciting antioxidant defenses. If the antioxidant defenses are insufficient to detoxify the ROS, then an increased mtDNA mutation rate can result.

Animals↗
PubMed2000

Expression of Rattus norvegicus mtDNA in Mus musculus cells results in multiple respiratory chain defects.

The production of in vitro and in vivo models of mitochondrial DNA (mtDNA) defects is currently limited by a lack of characterized mouse cell mtDNA mutants that may be expected to model human mitochondrial diseases. Here we describe the creation of transmitochondrial mouse (Mus musculus) cells repopulated with mtDNA from different murid species (xenomitochondrial cybrids). The closely related Mus spretus mtDNA is readily maintained when introduced into M. musculus mtDNA-less (rho(0)) cells, and the resulting cybrids have normal oxidative phosphorylation (OXPHOS). When the more distantly related Rattus norvegicus mtDNA is transferred to the mouse nuclear background the mtDNA is replicated, transcribed, and translated efficiently. However, function of several OXPHOS complexes that depend on the coordinated assembly of nuclear and mtDNA-encoded proteins is impaired. Complex I activity in the Rattus xenocybrid was 46% of the control mean; complex III was 37%, and complex IV was 78%. These defects combined to restrict maximal respiration to 12-31% of the control and M. spretus xenocybrids, as measured polarographically using isolated cybrid mitochondria. These defects are distinct to those previously reported for human/primate xenocybrids. It should be possible to produce other mouse xenocybrid constructs with less severe OXPHOS phenotypes, to model human mtDNA diseases.

Animals↗
PubMed2003

Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1.

Exposure to bacterial lipopolysaccharide (LPS) in vivo damages mitochondrial DNA (mtDNA) and interferes with mitochondrial transcription and oxidative phosphorylation (OXPHOS). Because this damage accompanies oxidative stress and is reversible, we postulated that LPS stimulates mtDNA replication and mitochondrial biogenesis via expression of factors responsive to reactive oxygen species, i.e. nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A. In testing this hypothesis in rat liver, we found that LPS induces NRF-1 protein expression and activity accompanied by mRNA expression for mitochondrial transcription factor-A, mtDNA polymerase gamma, NRF-2, and single-stranded DNA-binding protein. These events restored the loss in mtDNA copy number and OXPHOS gene expression caused by LPS and increased hepatocyte mitotic index, nuclear cyclin D1 translocation, and phosphorylation of pro-survival kinase, Akt. Thus, NRF-1 was implicated in oxidant-mediated mitochondrial biogenesis to provide OXPHOS for proliferation. This implication was tested in novel mtDNA-deficient cells generated from rat hepatoma cells that overexpress NRF-1. Depletion of mtDNA (rhoo clones) diminished oxidant production and caused loss of NRF-1 expression and growth delay. NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage.

Active Transport, Cell Nucleus↗
PubMed2004

Replacement of amino acid sequence features of a- and c-subunits of ATP synthases of Alkaliphilic Bacillus with the Bacillus consensus sequence results in defective oxidative phosphorylation and non-fermentative growth at pH 10.5.

Mitchell's (Mitchell, P. (1961) Nature 191, 144-148) chemiosmotic model of energy coupling posits a bulk electrochemical proton gradient (Deltap) as the sole driving force for proton-coupled ATP synthesis via oxidative phosphorylation (OXPHOS) and for other bioenergetic work. Two properties of proton-coupled OXPHOS by alkaliphilic Bacillus species pose a challenge to this tenet: robust ATP synthesis at pH 10.5 that does not correlate with the magnitude of the Deltap and the failure of artificially imposed potentials to substitute for respiration-generated potentials in energizing ATP synthesis at high pH (Krulwich, T. (1995) Mol. Microbiol. 15, 403-410). Here we show that these properties, in alkaliphilic Bacillus pseudofirmus OF4, depend upon alkaliphile-specific features in the proton pathway through the a- and c-subunits of ATP synthase. Site-directed changes were made in six such features to the corresponding sequence in Bacillus megaterium, which reflects the consensus sequence for non-alkaliphilic Bacillus. Five of the six single mutants assembled an active ATPase/ATP synthase, and four of these mutants exhibited a specific defect in non-fermentative growth at high pH. Most of these mutants lost the ability to generate the high phosphorylation potentials at low bulk Deltap that are characteristic of alkaliphiles. The aLys(180) and aGly(212) residues that are predicted to be in the proton uptake pathway of the a-subunit were specifically implicated in pH-dependent restriction of proton flux through the ATP synthase to and from the bulk phase. The evidence included greatly enhanced ATP synthesis in response to an artificially imposed potential at high pH. The findings demonstrate that the ATP synthase of extreme alkaliphiles has special features that are required for non-fermentative growth and OXPHOS at high pH.

Adenosine Triphosphatases↗
PubMed2004

Mitochondrial disorders.

In the medical literature the term 'mitochondrial disorders' is to a large extent applied to the clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism, i.e. oxidative phosphorylation (OXPHOS). Faulty oxidative phosphorylation may be due to overall dysfunction of the respiratory chain, a heteromultimeric structure embedded in the inner mitochondrial membrane, or can be associated with single or multiple defects of the five complexes forming the respiratory chain itself. From the genetic standpoint, the respiratory chain is a unique structure of the inner mitochondrial membrane formed by means of the complementation of two separate genetic systems: the nuclear genome and the mitochondrial genome. The nuclear genome encodes the large majority of the protein subunits of the respiratory complexes and most of the mitochondrial DNA (mtDNA) replication and expression systems, whereas the mitochondrial genome encodes only 13 respiratory complex subunits, and some RNA components of the mitochondrial translational apparatus. Accordingly, mitochondrial disorders due to defects in OXPHOS include both mendelian-inherited and cytoplasmic-inherited diseases. This review describes human genetic diseases associated with mtDNA and nuclear DNA mutations leading to impaired OXPHOS.

Adult↗
PubMed2003

Mitochondrial complex I is deficient in renal oncocytomas.

Renal oncocytomas are benign tumors characterized by dense accumulation of mitochondria the cause of which remains unknown so far. Consistently, mitochondrial DNA content and the amounts and catalytic activities of several oxidative phosphorylation (OXPHOS) complexes were known to be increased in these tumors, but it was not ascertained that the OXPHOS system was functional. Here we investigated mitochondrial complex I and found that its NADH dehydrogenase activity and protein content were specifically decreased in oncocytomas, in stark contrast with the parallel decrease of all respiratory chain complexes in other, malignant, renal tumors. We conclude that deficiency of complex I in oncocytomas might be the early event causing the increased mitochondrial biogenesis, attempting to compensate for the loss of OXPHOS function. Since other tumors were found to be linked to mitochondrial deficiencies like genetic alterations of fumarate hydratase or succinate dehydrogenase, oncocytoma could be the third type of benign tumor associated with impairment of mitochondrial ATP production in an oxidative, quiescent tissue. Besides, complex I enzyme activity was moderately decreased in the vicinity of oncocytomas, when compared with normal tissue adjacent to other renal tumors. This suggested that oncocytomas are the result of at least two serial modifications altering the mitochondrial respiratory chain.

Adenoma, Oxyphilic↗
PubMed2001

Diabetes and nutrition: the mitochondrial part.

Diabetes mellitus is the most common genetic disease in the Western world today. It is the phenotype for >150 genotypes. Each of these genotypes is characterized by impaired glucose tolerance and impaired control of intermediary metabolism. There are many strains of mice and rats that can be used to study diabetes in its various forms. One of these is the BHE/Cdb rat, which mimics the human phenotype with a mutation in the mitochondrial (mt) DNA. The result of such mutation is a loss in metabolic control with respect to the role of the mitochondria in this control. This review addresses those aspects of control that are exerted by mt oxidative phosphorylation (OXPHOS). Diet can have both genomic and nongenomic effects on OXPHOS. The type of dietary fat influences the fluidity of the mt membranes and hence, mt function. The dietary fat effect depends on the genetic background of the consumer. Diabetes-prone BHE/Cdb rats with base substitutions in the mt ATPase 6 gene are more likely to be influenced by the diet effect on mt membrane fluidity than are normal rats. Vitamin A also affects mt function through an effect on mt gene expression. BHE/Cdb rats have a greater need for vitamin A than normal rats and supplemental vitamin A appears to influence OXPHOS.

Adenosine Triphosphatases↗
PubMed2003

Mitochondrial encephalomyopathies.

Mitochondrial encephalomyopathies are diseases caused by defective oxidative phosphorylation (OXPHOS), and affect the nervous system and/or skeletal muscle. They have emerged as a major entity among the neurometabolic diseases of childhood with an incidence of 1 in 11,000 children, and also have a high prevalence in adults. The first pathogenic mutation of human mitochondrial DNA (mtDNA) was discovered in 1988. Since then more than 100 mutations of mtDNA have been reported, including point mutations of genes encoding transfer RNA, ribosomal RNA, and proteins, as well as large-scale deletions. The first nuclear-DNA gene mutation causing OXPHOS disease was described in 1995. Mutations in nuclear genes may affect the respiratory chain by various mechanisms. Pathogenic mutations of nuclear-DNA-encoded subunits of complex I and II have been demonstrated as have mutations of respiratory chain assembly proteins. Several nuclear genes associated with mtDNA maintenance have been found to be associated with mitochondrial disorders since mutations in these genes predispose to multiple mtDNA deletions and/or reduced copy number of mtDNA. The genotype-phenotype correlation is not yet entirely clear, but new animal models will enhance our ability to study the pathophysiology of OXPHOS disorders.

Animals↗
PubMed2004

Fast adaptive coevolution of nuclear and mitochondrial subunits of ATP synthetase in orangutan.

Nuclear and mitochondrial genomes have to work in concert to generate a functional oxidative phosphorylation (OXPHOS) system. We have previously shown that we could restore partial OXPHOS function when chimpanzee or gorilla mitochondrial DNA (mtDNA) were introduced into human cells lacking mtDNA. However, we were unable to maintain orangutan mitochondrial DNA in a human cell. We have now produced chimpanzee, gorilla, orangutan, and baboon cells lacking mtDNA and attempted to introduce mtDNA from different apes into them. Surprisingly, we were able to maintain human mtDNA in an orangutan nuclear background, even though these cells showed severe OXPHOS abnormalities, including a complete absence of assembled ATP synthetase. Phylogenetic analysis of complex V mtDNA-encoded subunits showed that they are among the most evolutionarily divergent components of the mitochondrial genome between orangutan and the other apes. Our studies showed that adaptive coevolution of nuclear and mitochondrial components in apes can be fast and accelerate in recent branches of anthropoid primates.

Animals↗
PubMed1998

mtDNA replicative potential remains constant during ageing: polymerase gamma activity does not correlate with age related cytochrome oxidase activity decline in platelets.

Progressive age-related oxidative phosphorylation (OxPhos) decline is well known in human tissues. Depletion of mitochondrial DNA (mtDNA) causes OxPhos defects in patients with myopathic syndromes and deficient mtDNA replication has been observed in cells cultured from patients with mitochondrial disease. Patients undergoing treatment for AIDS develop OxPhos defects via mtDNA depletion resulting from inhibition of mtDNA polymerase gamma (Polgamma) by 2'-deoxy 3'-azido thymidine. These findings by others give rise to a possible link between mtDNA replication and bioenergetic decline in disease and during ageing. We have designed an in vitro assay for Polgamma function in small tissue samples to explore this possible link. Platelet homogenate Polgamma showed an activity with a K m of 150 microM (dTTP), a V max of 11.8 pmol/min/mg, inhibited (41% inhibition; 50 microM) by ethidium bromide. Determination of several storage characteristics showed that platelets were a convenient source of Polgamma for assay. Polgamma activity in 45 subjects did not coincide with significant age-related decline (P<0.002; P) observed in cytochrome oxidase (CytOx) activity or with citrate synthase activity. Of the activities studied, the only significant age-wise variation was a 24% CytOx deficiency in elderly (>50; n = 19) compared to young (<51; n = 24) individuals (P<0.01; t). These results suggest a maintenance of total cellular mtDNA Polgamma processive levels during ageing, largely independent of total cellular bioenergetic status or mitochondrial number/density. The processive component of Polgamma is therefore unlikely to make a major contribution to age-related bioenergetic activity decline. This does not, however, preclude the possibility that transient periods of inhibition at crucial points of the cell cycle or development may augment existing intracellular deficiencies. The assay described here greatly facilitates study of Polgamma activity in patients with conditions involving mtDNA depletion or rearrangement.

Adult↗
PubMed2006

Not only insulin stimulates mitochondriogenesis in muscle cells, but mitochondria are also essential for insulin-mediated myogenesis.

Viability and myogenesis from C2C12 muscle cells and L6 rat myoblasts were dose-dependently stimulated by insulin. The metabolic inhibitors of phosphatidyl-inositol-3-kinase (PI-3K, LY294002) and of MAPKK/ERK kinase (MEK, PD98059) differently affected insulin-stimulated myogenesis of the cells. After LY294002 and PD98059 treatment, viability deteriorated and apparently an additive effect of both metabolic inhibitors was observed, irrespective of the method of measurement (neutral red or MTT assay). These inhibitors were antagonistic in myogenesis. Our results confirm that insulin regulates cell viability by at least two distinct pathways, namely by PI-3K- and MEK-dependent signalling cascades. Both pathways are agonistic in cell viability, whereas PI-3K rather than MEK supports insulin-mediated myogenicity. Accordingly, inhibition of insulin action by LY294002, but not PD98059, was accompanied with a reduced level of Ser473-phosphorylated Akt with additional loss of myogenin protein. Besides, repression of insulin signalling by either PI-3K or MEK inhibitor diminished expression of selected subunits of the mitochondrial oxidative phosphorylation enzymes (OXPHOS). In turn, insulin raised and accelerated protein expression of subunits I and IV of mitochondrial cytochrome-c oxidase (COX). In addition, the level of myogenin, the molecular marker of terminal and general muscle differentiation indices decreased if selected OXPHOS enzymes were individually blocked by rotenone, myxothiazol or oligomycin. Summing up, our results pointed to mitochondria as an essential organelle for insulin-dependent myogenesis. Insulin positively affects mitochondrial function by induction of OXPHOS enzymes, which provide energy indispensable for the anabolic effect of insulin.

Animals↗
PubMed2003

The effects of steroid hormones on the transcription of genes encoding enzymes of oxidative phosphorylation.

Regulation of energy metabolism is one of the major functions of steroid hormones. In this process, mitochondria, by way of oxidative phosphorylation, play a central role. Depending on the energy needs of the cell, on the tissue, on the developmental stage and on the intensity of the hormonal stimulus, the response can be an activation of pre-existing respiratory chain components, an increased transcription of nuclear-encoded and/or mitochondrial-encoded respiratory chain enzyme (OXPHOS) genes and of biosynthesis of the respective enzyme subunits or, in extreme cases of high energy needs, an increase in the number of mitochondria and mitochondrial DNA content per cell. Some of the hormonally regulated systems involving effects on nuclear and mitochondrial OXPHOS genes are reviewed in this paper. The possible molecular mechanisms of steroid hormone action on nuclear and mitochondrial gene transcription and possible ways of coordination of transcription in these two separate cell compartments involving direct interaction of steroid receptors with hormone response elements in nuclear OXPHOS genes and in mitochondria and induction/activation of nuclear-encoded regulatory factors affecting mitochondrial gene transcription are presented.

Animals↗
PubMed2006

Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency.

BACKGROUND: Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA. OBJECTIVE: To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying genetic defect. RESULTS: Three novel non-synonymous substitutions in protein-coding genes, 4681T-->C in MT-ND2, 9891T-->C in MT-CO3 and 14122A-->G in MT-ND5, and one novel substitution in the 12S rRNA gene, 686A-->G, were found. The definitely pathogenic mutation 3460G-->A was identified in an 18-year-old woman who had severe isolated complex I deficiency and progressive myopathy. CONCLUSIONS: Bioinformatic analyses suggest a pathogenic role for the novel 4681T-->C substitution found in a boy with Leigh's disease. These results show that the clinical phenotype caused by the primary Leber's hereditary optic neuropathy mutation 3460G-->A is more variable than has been thought. In the remaining 23 patients, the role of mtDNA mutations as a cause of the OXPHOS system deficiency could be excluded. The deficiency in these children probably originates from mutations in the nuclear genes coding for respiratory enzyme subunits or assembly factors.

Adolescent↗
PubMed2006

Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.

Increased conversion of glucose to lactic acid associated with decreased mitochondrial respiration is a unique feature of tumors first described by Otto Warburg in the 1920s. Recent evidence suggests that the Warburg effect is caused by oncogenes and is an underlying mechanism of malignant transformation. Using a novel approach to measure cellular metabolic rates in vitro, the bioenergetic basis of this increased glycolysis and reduced mitochondrial respiration was investigated in two human cancer cell lines, H460 and A549. The bioenergetic phenotype was analyzed by measuring cellular respiration, glycolysis rate, and ATP turnover of the cells in response to various pharmacological modulators. H460 and A549 cells displayed a dependency on glycolysis and an ability to significantly upregulate this pathway when their respiration was inhibited. The converse, however, was not true. The cell lines were attenuated in oxidative phosphorylation (OXPHOS) capacity and were unable to sufficiently upregulate mitochondrial OXPHOS when glycolysis was disabled. This observed mitochondrial impairment was intimately linked to the increased dependency on glycolysis. Furthermore, it was demonstrated that H460 cells were more glycolytic, having a greater impairment of mitochondrial respiration, compared with A549 cells. Finally, the upregulation of glycolysis in response to mitochondrial ATP synthesis inhibition was dependent on AMP-activated protein kinase activity. In summary, our results demonstrate a bioenergetic phenotype of these two cancer cell lines characterized by increased rate of glycolysis and a linked attenuation in their OXPHOS capacity. These metabolic alterations provide a mechanistic explanation for the growth advantage and apoptotic resistance of tumor cells.

AMP-Activated Protein Kinases↗
PubMed1999

Oligomycin sensitivity of mitochondrial F(1)F(0)-ATPase in diabetes-prone BHE/Cdb rats.

BHE/Cdb and Sprague-Dawley rats differ in their mitochondrial DNA sequence for the ATPase 6 ("subunit a") gene. Base substitutions in this sequence result in the substitution of asparagine for aspartate at position 101 and the substitution of serine for leucine at position 129. Differences in sensitivity to oligomycin were observed. When the isolated F(1)F(0)-ATPase complex was studied and ATPase activity was assessed, that which was isolated from the BHE/Cdb rats was less sensitive to oligomycin inhibition than that which was isolated from the Sprague-Dawley rats. In contrast, when oxygen consumption was measured [oxygen phosphorylation (OXPHOS)] and a dose-response curve was generated with isolated mitochondria from these two strains, there was a shift to the left for the BHE/Cdb rat mitochondria. These mitochondria were more sensitive to oligomycin inhibition of OXPHOS than were mitochondria isolated from Sprague-Dawley rats. The OXPHOS results are consistent with those from human fibroblasts having either a normal or mutated ATPase 6 gene.

Animals↗
PubMedDate not supplied

Mitochondrial function and alzheimer's disease.

The brain is highly dependent on aerobic metabolism. Normal mitochondrial function is therefore likely to play a critical role in neuronal function and integrity. Defects in the mitochondrial oxidative phosphorylation pathway (OXPHOS) have been demonstrated in aging human tissue including brain. It is not clear whether underlying mitochondrial DNA mutations are responsible for the observed functional defects. The previously reported OXPHOS defects, in particular reduced cytochrome c oxidase activity, in Alzheimer's disease (AD) are not likely to be due to specific enzyme dysfunction. The falloff in cytochrome c oxidase activity in AD brains is more likely to be related to a global decline in mitochondrial activity manifested by downregulation in mitochondrial number. It is not definitely established where the observed mitochondrial changes are placed in the AD cascade. A number of factors might contribute to the observed changes in OXPHOS function including mitochondrial transport through axonal and dendritic processes, compromised regulatory feedback mechanisms responsible for individual complex-subunit synthesis, and complex assembly.

Aging↗