SEARCH · Search PubMed

Results for “mitochondrial dysfunction”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,387 records · Page 77Linked to original sources

PubMed1999

Novel cobalt complex inhibitors of mitochondrial calcium uptake.

Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.

Animals↗

PubMed2005

Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia.

Several clinical, genetic and neuroimaging studies implicate mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. It has been reported that a mitochondrial DNA (mtDNA) deletion of 4,977 bp, known as the 'common deletion', is associated with both mental illnesses. A lack of normal age-related accumulation of this deletion in schizophrenia and increased occurrence of the common deletion in bipolar disorder have been reported. However, even in the affected bipolar samples, the levels of common deletion were relatively small, indicating that the common deletion did not play a pathophysiological role in respiratory function. We hypothesized that accumulation of multiple mtDNA deletions, rather than the common deletion alone, is involved in the pathophysiology of these two major mental disorders. To test this hypothesis, we assessed mtDNA deletion(s) by comparing the copy number of two regions in mtDNA -- ND1 and ND4 -- using real-time quantitative PCR in the frontal cortex of 84 subjects (30 control, 27 with bipolar disorder, and 27 with schizophrenia). We also assessed the relative amount of mtDNA vs. nuclear DNA and the expression level of DNA polymerase gamma (POLG), which is involved in replicating mtDNA. We observed no association between mtDNA deletions and the two major mental disorders in the frontal cortex, which did not support our hypothesis. We did, however, make the following observations, although they were not significant after Bonferroni correction: (1) the ratio of mtDNA to nuclear DNA was significantly higher in female patients with schizophrenia than in control females ( p =0.040) and (2) in bipolar disorder, the relative amount of mtDNA decreased with age ( p =0.016). furthermore, POLG expression was significantly up-regulated in bipolar disorder ( p =0.036). Our results suggest that abnormalities in the system maintaining replication of mtdna may underlie bipolar disorder and schizophrenia.

Adult↗

PubMed2000

Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes.

Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.

Adenosine Triphosphate↗

PubMed2005

Postprandial insulin response and mitochondrial oxidation in obese men nutritionally treated to lose weight.

Obesity, hyperglycemia, and insulin resistance have been associated to an oxidative mitochondrial dysfunction. The aim of this research was to evaluate the relation between carbohydrate metabolism and mitochondrial oxidation, as affected by the weight status and the weight loss induced by a calorie-restricted diet. Lean control men (BMI<25 kg/m2, n = 6) and obese men (BMI>30 kg/m2, n = 14), who were characterized as insulin resistant (n = 6) or insulin sensitive (n = 8) based on HOMA index values, participated in the trial. Plasma insulin levels and mitochondrial oxidation estimated by the 2-keto(1-13C)isocaproate breath test, were measured after ingestion of a test meal during 3 h. Obese subjects repeated the breath test protocol after a 10-week caloric restriction diet to lose weight. Postprandial insulin secretion tended to be marginally higher (P = 0.059) in both obese groups than in controls, while the rate of postprandial mitochondrial oxidation was markedly decreased (P = 0.019) in the obese subjects as compared with lean individuals. The nutritionally induced weight loss produced a rise in the postprandial oxidative process in volunteers initially considered as insulin resistant (P = 0.036), while no statistical differences in the insulin-sensitive obese (P = 0.241) were found. Interestingly, the percentage of oxidized tracer was inversely related to postprandial insulin secretion (r = -0.56; P = 0.001). In conclusion, these results support the hypothetized relation between carbohydrate metabolism and mitochondrial oxidation at a postprandial state in obese subjects, raising interest about mitochondria stimulation as a target in the therapy of obesity.

Adult↗

PubMed2000

NMR spectroscopy and imaging of the neonatal brain.

Magnetic resonance spectroscopy and imaging provide unique information about the brain to the biochemist and the clinician. In particular, the ability to image metabolites other than water and to get detailed information about dynamic cellular processes (such as blood flow, blood oxygenation and cell swelling) is leading to many new insights into brain function and dysfunction. This review describes the use of old and new NMR techniques which demonstrate that mitochondrial dysfunction plays an important role in the cell death that occurs following an hypoxic-ischaemic insult to the neonatal brain.

Adenosine Triphosphate↗

PubMed2004

Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover.

Inhibition of proteasome activity occurs in normal aging and in a wide variety of neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. Although each of these conditions is also associated with mitochondrial dysfunction potentially mediated by proteasome inhibition, the relationship between proteasome inhibition and the loss of mitochondrial homeostasis in each of these conditions has not been fully elucidated. In this study, we conducted experimentation in order to begin to develop a more complete understanding of the effects proteasome inhibition has on neural mitochondrial homeostasis. Mitochondria within neural SH-SY5Y cells exposed to low level proteasome inhibition possessed similar morphological features and similar rates of electron transport chain activity under basal conditions as compared with untreated neural cultures of equal passage number. Despite such similarities, maximal complex I and complex II activities were dramatically reduced in neural cells subject to proteasome inhibition. Proteasome inhibition also increased mitochondrial reactive oxygen species production, reduced intramitochondrial protein translation, and increased cellular dependence on glycolysis. Finally, whereas proteasome inhibition generated cells that consistently possessed mitochondria located in close proximity to lysosomes with mitochondria present in the cellular debris located within autophagosomes, increased levels of lipofuscin suggest that impairments in mitochondrial turnover may occur following proteasome inhibition. Taken together, these data demonstrate that proteasome inhibition dramatically alters specific aspects of neural mitochondrial homeostasis and alters lysosomal-mediated degradation of mitochondria with both of these alterations potentially contributing to aging and age-related disease in the nervous system.

Animals↗

PubMed2002

Induction of an unregulated channel by mutations in adenine nucleotide translocase suggests an explanation for human ophthalmoplegia.

Adenine nucleotide translocase (Ant) is primarily involved in ATP/ADP exchange across the mitochondrial inner membrane. Recently, the A114P missense mutation in the human Ant1 protein was found to be associated with autosomal dominant progressive external ophthalmoplegia (adPEO). Ant1(A114P) was proposed to cause an imbalance of the mitochondrial deoxynucleotide pool that subsequently affects the accuracy of mtDNA replication, thereby leading to accumulation of mutant mtDNA. In the present study, it has been shown that the A128P mutation of the Saccharomyces cerevisiae Aac2 protein, equivalent to A114P in human Ant1p, does not always affect respiratory growth. However, expression of aac2(A128P) results in depolarization, structural swelling and disintegration of mitochondria, and ultimately an arrest of cell growth in a dominant-negative manner. The aac2(A128P) mutation likely induces an unregulated channel allowing free passage of solutes across the inner membrane. These data raise the possibility that the formation of an unregulated channel, rather than a defect in ATP/ADP exchange, is a direct pathogenic factor in human adPEO. The accumulation of mtDNA mutations might be a consequence of mitochondrial dysfunction.

Adenine Nucleotide Translocator 1↗

PubMed2003

Mitochondrial impairment in p53-deficient human cancer cells.

The mechanism linking p53 inactivation to human cell malignancy remains unclear. Studies have indicated that mitochondrial dysfunction is involved in carcinogenesis. In this study we investigated the role of p53 in mitochondrial DNA (mtDNA) mutation and maintenance of proper mitochondrial function. We measured mtDNA mutation and found no difference in frequency of mutation between the p53(+/+) and p53(-/-) cell lines. However, mitochondrial cytochrome c oxidase (COX) activity was significantly diminished in p53(-/-) cells. This decrease in COX activity was attributed to decreased protein levels of the COXII subunit encoded by the mitochondrial genome and was not due to mutation in the mitochondrial COXII gene. Further investigation revealed no concomitant decrease in COXII mRNA levels in p53(-/-) cells and the stability of mRNA in p53(-/-) cells was unaffected. This study suggests that decreased COX activity is likely due to post-transcriptional regulation of the COXII subunit by p53. COX is a critical enzyme in the mitochondrial electron transport chain and reduced COX activity may affect mitochondrial structure. However, examination of mitochondrial ultrastructure revealed no obvious differences between p53(+/+) and p53(-/-) cell lines. Together, our study suggests that p53 is involved in regulation of COXII at the protein level but not at the mRNA level. p53 does not affect mtDNA mutation or mitochondrial ultrastructure.

Colonic Neoplasms↗

PubMed2000

Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?

Nucleoside reverse transcriptase inhibitors suppress HIV replication by blocking reverse transcriptase, an RNA-dependent DNA polymerase. These drugs can also affect cellular and mitochondrial DNA polymerases. Mitochondrial DNA polymerase gamma is particularly sensitive to nucleoside reverse transcriptase inhibitors, and the majority of adverse effects caused by nucleoside reverse transcriptase inhibitors are most likely caused by mitochondrial dysfunction. This article reviews the recent clinical implications of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity and discusses options for management.

Journal Article↗

PubMed2000

The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited.

1-Methyl-4-phenylpyridinium (MPP(+)) is selectively toxic to dopaminergic neurons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP(+) toxicity and the pathogenesis of PD. MPP(+) can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochondrial depolarization and generation of reactive oxygen species. However, MPP(+) toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, we examined the effects of MPP(+) on survival, mitochondrial membrane potential (DeltaPsim), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP(+) (5 microM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their DeltaPsim. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP(+) to dopaminergic neurons, depolarized DeltaPsim to a greater extent than MPP(+). In addition, neither rotenone nor MPP(+) increased superoxide in dopaminergic neurons, and MPP(+) failed to alter levels of reduced glutathione. Therefore, we conclude that increased superoxide and loss of DeltaPsim may not represent primary events in MPP(+) toxicity, and complex I inhibition alone is not sufficient to explain the selective toxicity of MPP(+) to dopaminergic neurons. Clarifying the effects of MPP(+) on energy metabolism may provide insight into the mechanism of dopaminergic neuronal degeneration in PD.

1-Methyl-4-phenylpyridinium↗

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↗

PubMed1989

Mitochondrial myopathies: morphological and biochemical studies in human muscle cultures.

The mitochondrial myopathies are a heterogeneous group of disorders presumed to be caused by primary mitochondrial dysfunction with impairment of energy provision from oxidative metabolism. An increasing number of specific functional mitochondrial deficiencies have been documented and recently new strategies are beginning to analyze molecular and genetic mechanisms. Nevertheless these specific disorders have not been studied extensively in human muscle cultures. The objectives of our study were to reproduce morphological and biochemical changes in cultured myotubes of three Kearns-Sayre syndrome (KSS) patients to evidentiate a different mitochondrial susceptibility to 2-4 dinitrophenol (DNP) into normal and KSS muscle cultures, and to investigate the protective effect of ubidecarenone (Q10) on KSS myotubes exposed to DNP. In KSS cultures as compared to normal ones no abnormalities in growth pattern and differentiation were observed. KSS myotubes DNP exposed showed some abnormally large mitochondria with parallel-packed cristae and decrement in all mitochondrial enzymes activity ranging from 20 to 40%. In normal myotubes DNP exposed and in patient cultures DNP-Q10 treated a normal mitochondrial morphology and a recovery of enzymatic activity was found. In Complex I deficiency patient cultured myotubes cytochemical, immunocytochemical, ultrastructural and biochemical studies were performed and no abnormalities were found. Negative tissue culture findings could be explained by the fact that the defect cannot be reproduced in aneural cultures, and that there could be a gradual selection of cells containing a preponderance of wild type mitochondria over those that contain mutant mitochondria.

Cells, Cultured↗

PubMed2003

Mechanism of primary Cd2+-induced rat liver mitochondria dysfunction: discrete modes of Cd2+ action on calcium and thiol-dependent domains.

We attempted to discern discrete sites of Cd2+ deleterious action on rat liver mitochondrial function. In particular, EGTA, ADP, and cyclosporin A (potent mitochondrial permeability transition antagonists) affected mainly Cd2+-induced changes in resting state respiration, eliminating its stimulation in KCl medium, while dithiothreitol (DTT, a dithiol reductant) produced its effect both on Cd2+ activation of the basal respiration and Cd2+ depression of uncoupler-stimulated respiration, evoking its restoration. Substantial differences in DTT influence on mitochondrial respiration at low and high [Cd2+] were revealed, namely, an enhanced mitochondrial permeabilization in the presence of saturated [DTT] at high [Cd2+] took place. Besides, DTT only partially reversed Cd2+-induced swelling in NH4NO3 medium when glutamate plus malate or succinate without rotenone was used. Contrarily, DTT produced complete reversal of the swelling of succinate-energized mitochondria when rotenone was present in the medium. In addition, in the presence of rotenone both Cd2+-produced activation of the resting state respiration in KCl medium and Cd2+-induced swelling in sucrose medium of succinate-energized mitochondria were more sensitive to cyclosporin A than the same Cd2+ effects obtained on mitochondria oxidizing succinate (without rotenone) or glutamate plus malate. We have concluded that Cd2+, producing primary mitochondrial dysfunction, acts both as a thiol and Me2+ binding site reagent. Suppositions about possible localization of separate sites of direct Cd2+ effects on mitochondrial function were made.

Adenosine Diphosphate↗

PubMed2006

Identification of calcium-independent phospholipase A2gamma in mitochondria and its role in mitochondrial oxidative stress.

Oxidant-induced lipid peroxidation and cell death mediate pathologies associated with ischemia-reperfusion and inflammation. Our previous work in rabbit renal proximal tubular cells (RPTC) demonstrated that inhibition of Ca(2+)-independent phospholipase A(2) (iPLA(2)) potentiates oxidant-induced lipid peroxidation and necrosis, implicating iPLA(2) in phospholipid repair. This study was conducted to identify a RPTC mitochondrial PLA(2) and determine the role of PLA(2) in oxidant-induced mitochondrial dysfunction. iPLA(2) activity was detected in Percoll-purified rabbit renal cortex mitochondria (RCM) and in isolated mitochondrial inner membrane fractions from rabbit and human RCM. Immunoblot analysis and inhibitor sensitivity profiles revealed that iPLA(2)gamma is the RCM iPLA(2) activity. RCM iPLA(2) activity was enhanced in the presence of ATP and was blocked by the PKCepsilon V1-2 inhibitor. Oxidant-induced mitochondrial lipid peroxidation and swelling were accelerated by pretreatment with R-BEL, but not S-BEL. Furthermore, oxidant treatment of isolated RCM resulted in decreased iPLA(2)gamma activity. These results reveal that RCM iPLA(2) is iPLA(2)gamma, RCM iPLA(2)gamma is regulated by phosphorylation by PKCepsilon, iPLA(2)gamma protects RCM from oxidant-induced lipid peroxidation and dysfunction, and that a strategy to preserve or enhance iPLA(2)gamma activity may be of therapeutic benefit.

Animals↗

PubMed1996

Immunoreactivity for brain-fatty acid binding protein in gomori-positive astrocytes.

Gomori-positive (GP) astrocytes are a subset of brain astrocytes with highly stained cytoplasmic granules that arise from the degradation of mitochondria. The GP granules of these astrocytes are most prominent in the arcuate nucleus of the hypothalamus, but can also be detected in the olfactory bulbs, hippocampus, habenula, and other selected brain regions. The cause and functional effects of this mitochondrial pathology in these glia are not yet known with certainty. In other tissues, mitochondrial dysfunction is associated with elevations in cytoplasmic lipids and lipid-binding proteins, due to impaired mitochondrial oxidation of lipids. To see if GP astrocytic mitochondrial pathology is also associated with an elevation in lipid binding proteins, rat brain sections were stained for brain fatty acid binding protein (B-FABP), using immunocytochemistry. Astrocytes immunoreactive for B-FABP were much more abundant in brain regions enriched in GP astrocytes than in other brain regions. Semi-thin sections revealed that astrocytic B-FABP immunoreactivity was often, but not always, associated with GP cytoplasmic granules. These data suggest that GP astrocytes have an unusual lipid metabolism, which may relate to degenerative processes occurring in the selected brain regions that contain GP astrocytes.

Animals↗

PubMed1995

Enhanced induction of the mitochondrial permeability transition following acute menadione administration.

Induction of the mitochondrial permeability transition in vitro is well-characterized and widely implicated in the mechanism of oxidant-induced cell death. Despite an abundance of in vitro evidence, implication of mitochondrial dysfunction in the mechanism of chemical toxicity in vivo awaits demonstration of the induction of the mitochondrial permeability transition in tissues from intoxicated animals. Menadione (2-methyl-1,4-naphthoquinone), an agent known to induce the permeability transition in isolated liver mitochondrial in vitro, was administered as a single bolus to adult male rats, and hepatic mitochondria were isolated 24 h later. Mitochondria from menadione-treated rats exhibited an increased sensitivity to calcium-induced inhibition of state 3 respiration and loss of respiratory control, as well as a greater sensitivity to calcium-induced calcium release that was inhibited by cyclosporine A. Associated with this was the depolarization of membrane potential and swelling of mitochondria from menadione-treated animals, but not control animals. Both the calcium-dependent depolarization and swelling of mitochondria from menadione-treated rats were inhibited by adding either cyclosporine A or ruthenium red. The results are consistent with the induction of the mitochondrial permeability transition and provide the first evidence for the manifestation of an increased sensitivity to this response as a result of chemical exposure in vivo.

Animals↗

PubMed2005

L-carnitine inhibits hypoglycemia-induced brain damage in the rat.

Hypoglycemia sometimes occurs in patients with diabetes mellitus who receive excessive doses of insulin. Severe hypoglycemia has been known to induce mitochondrial swelling followed by neuronal death in the brain. Since L-carnitine effectively preserves mitochondrial function in various cells both in vitro and in vivo, we investigated its effects on the neuronal damage induced by hypoglycemic insult in male Wistar rats. Animals were given L-carnitine-containing water (0.1%) for 1 week and then received insulin (20 U/kg, i.p.) to induce hypoglycemia. Although L-carnitine did not affect the mortality of animals that developed hypoglycemic shock, it improved the cognitive function of the survived animals as assessed by the Morris water-maze test. L-carnitine effectively inhibited the increase in oxidized glutathione and mitochondrial dysfunction in the hippocampus and prevented neuronal injury. L-carnitine also inhibited the decrease in mitochondrial membrane potential and the generation of reactive oxygen species in hippocampal neuronal cells cultured in glucose-deprived medium. These results suggest that L-carnitine prevents hypoglycemia-induced neuronal damage in the hippocampus, presumably by preserving mitochondrial functions. Thus, L-carnitine may have therapeutic potential in patients with hypoglycemia induced by insulin overdose.

Aldehydes↗

PubMed2006

Antimyoclonic effect of levetiracetam in MERRF syndrome.

The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF.

Activities of Daily Living↗