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Results for “Mitochondria dysfunction”

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At least 163 records · Page 9Linked to original sources

PubMed1996

Serum carnitine and disabling fatigue in multiple sclerosis.

The serum concentrations of total, free and acylcarnitine were compared in 25 patients with multiple sclerosis (MS) and among age- and sex-matched normal controls by the new enzymatic cycling method in order to clarify whether the fatigue in MS might be due to possible carnitine-related fatty acid metabolic abnormalities in the mitochondria of skeletal muscles. Patients with MS were divided into those with and those without excessive fatigue. Levels of total and free carnitine were not significantly different between MS patients and normal controls. Levels of acylcarnitine, whose decrease in chronic fatigue syndrome has been reported, were also similar between MS patients and normal controls. There was no difference in these carnitine levels between MS patients with and without excessive fatigue. We argue that acylcarnitine deficiency and fatty acid metabolic dysfunction in mitochondria are not relevant to the excessive fatigue in patients with MS, and further explanatory investigations are to be sought.

Adult↗

PubMed2001

Functional modification of cytochrome c by peroxynitrite in an electron transfer reaction.

The redox reaction of cytochrome c after modification with peroxynitrite under physiological conditions was investigated. Cytochrome c was treated with a bolus of synthetic peroxynitrite at a sub-millimolar concentration, and then subjected to reduction by superoxide and oxidation by hydrogen peroxide. The ability for the membrane potential formation in the mitochondrial respiratory chain was also evaluated. After the treatment with peroxynitrite, the cytochrome c molecule was mono-nitrated mainly at a tyrosine residue, using liquid chromatography-electrospray ionizing mass spectrometry (LC-ESI-MS) and HPLC. Although the redox capacity of cytochrome c was not affected by the peroxynitrite treatment, the oxidation of ferrocytochrome c to ferricytochrome c by hydrogen peroxide was accelerated. When cytochrome c was treated with peroxynitrite in the presence of 5-methoxytryptamine, an inhibitor for the tyrosine nitration by peroxynitrite, the acceleration of hydrogen peroxide-mediated oxidation was suppressed. It was also found that the formation of membrane potential in the rat liver mitochondria was suppressed when peroxynitrite-treated cytochrome c was used instead of the intact cytochrome c in vitro. From these results, we concluded that the peroxynitrite-treated cytochrome c was nitrated at a tyrosine residue and became more susceptible to oxidation by hydrogen peroxide, concomitantly losing the ability to transfer electrons in the mitochondrial respiratory chain. It is suggested that the peroxynitrite-induced modification of cytochrome c increases the susceptibility to non-physiological oxidants, and may cause dysfunction of mitochondria by suppressing of membrane potential.

Animals↗

PubMed2005

Mitochondria are involved in the neurogenic neuroprotection conferred by stimulation of cerebellar fastigial nucleus.

Activation of neural pathways originating in the cerebellar fastigial nucleus (FN) protects the brain from the deleterious effects of cerebral ischemia and excitotoxicity, a phenomenon termed central neurogenic neuroprotection. The neuroprotection is, in part, mediated by suppression of apoptosis. We sought to determine whether FN stimulation exerts its anti-apoptotic effect through mitochondrial mechanisms. Mitochondria were isolated from the cerebral cortex of rats in which the FN was stimulated for 1 h (100 microA; 1 s on/1 s off), 72 h earlier. Stimulation of the dentate nucleus (DN), a brain region that does not confer neuroprotection, served as control. Mitochondria isolated from FN-stimulated rats exhibited a marked increase in their ability to sequester Ca2+ and an increased resistance to Ca2+-induced membrane depolarization and depression in respiration. FN stimulation also leads to reduction in the release in cytochrome c, induced either by Ca2+ or the mitochondrial toxin mastoparan. Furthermore, in brain slices, FN stimulation reduced the staurosporine-induced insertion of the pro-apoptotic protein Bax into the mitochondria, a critical step in the mitochondrial mechanisms of apoptosis. Collectively, these results provide evidence that FN stimulation protects the mitochondria from dysfunction induced by Ca2+ loading, and inhibits mitochondrial pathways initiating apoptosis. These mitochondrial mechanisms are likely to play a role in the neuroprotection exerted by FN stimulation.

Animals↗

PubMed2024

Integrated multi-omics approaches reveal the neurotoxicity of triclocarban in mouse brain.

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood-brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.

Animals↗

PubMed2006

Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology.

In this article we summarise present knowledge on the role of pro-inflammatory cytokines on chronic inflammation leading to organismal aging, a phenomenon we proposed to call "inflamm-aging". In particular, we review genetic data regarding polymorphisms of genes encoding for cytokines and proteins involved in natural immunity (such as Toll-like Receptors and Heat Shock Proteins) obtained from large population studies including young, old and very old people in good health status or affected by age-related diseases such as Alzheimer's Disease and Type II Diabetes. On the whole, despite some controversial results, the available data are in favour of the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity. Further, we present a possible hypothesis to reconcile energetic dysfunction, including mitochondria, and inflamm-aging. New perspectives for future studies, including phylogenetic studies in animal models and in silico studies on mathematical and bioinformatic models inspired by the systems biology approach, are also proposed.

Aging↗

PubMed2004

[Effects of enteral supplementation with glutamine on mitochondria respiratory function of intestinal epithelium in burned rats].

OBJECTIVE: To investigate the effects of enteral supplementation with glutamine on mitochondria respiratory function of intestinal epithelium in burned rats. METHODS: Wistar rats inflicted with 30% total body surface area (TBSA) full thickness thermal injury were randomly divided into three groups, i.e. burn with enteral nutrition (EN), burn with glutamine treatment (GLN), and normal control (C) groups. Burned rats were infused 732.2 kJ.kg-1.d-1 solution for intravenous nutrition and oral administration, in which the supply energy ratio of glucose, fat and protein was 55:30:15 respectively, glucose was 15.3% and the proportion of calorie to nitrogen was 183:1. The following indices including respiratory control rate (RCR), oxygen extraction (Oext), P/O ratio and intestine mucosal blood flow (IMBF) were measured on postburn days 1, 3, 5, 7, 10. RESULTS: After burn injury, the RCR, Oext, P/O ratio, and IMBF were significant decreased in both EN and GLN groups, but all above indices were markedly increased in GLN group compared to those in EN group. CONCLUSION: After burn injury, the IMBF and Oext were declined, resulting in mitochondria respiratory oxidative dysfunction and phosphorylation discoupling in intestinal epithelium. GLN supplementation appears to be beneficial to improving IMBF, increasing Oext, abating the extent of mitochondria respiration dysfunction, and promoting oxidative phosphorylation.

Animals↗

PubMed1980

Effects of pentachlorophenol and 2,4,6-trichlorophenol on the disposition of sulfobromophthalein and respiration of isolated liver cells.

The effect of pentachlorophenol (PCP) and 2,4,6-tricholorphenol (2,4,6-T) on the disposition of the hepatodiagnostic dye, sulfobromophthalein (BSP) has been studied in isolated liver cells. PCP (4-6 microM) as well as 2,4,6-T (50-100 microM) interferes with the disposition of BSP. The main effect apparently occurs at the secretion step as both drugs severely impair the release of the glutathione conjugate of BSP into the medium. As a consequence, BSP and its conjugate accumulate in the cell. High doses of PCP did not increase the release of lactate dehydrogenase from the hepatocytes. Concentrations of the two phenols which interfere with the secretion of BSP also completely uncouple the oxidative phosphorylation of hepatocellular mitochondria. The dysfunction of liver cells described here may therefore be explained by the effect of PCP and 2,4,6-T on the energy production of the cells. The higher toxicity of PCP as compared to 2,4,6-T observed in our system corresponds well with the higher LD50 of the latter compound.

Animals↗

PubMed1989

Evidence for a mitochondrial lesion in cystic fibrosis.

Cystic fibrosis (CF) remains a major problem in human genetics and cell pathophysiology. It is a single gene trait caused by a mutation on the long arm of chromosome 7. Among its expressions are abnormal regulation of chloride channels and/or microobstructions in exocrine tissues. Here, evidence is presented that mitochondria are dysfunctional in CF: the major site of increased intracellular Ca in CF is mitochondrial, cells from subjects with CF consume more oxygen than normal, respond differentially to inhibitors of mitochondrial function, express increased electron transport activity and altered kinetics of complex I (NADH dehydrogenase) of the mitochondrial electron transport system. Patients with CF express increased total and resting energy expenditure. Some of these differences from normal occur also in asymptomatic carriers of the CF gene.

Calcium↗

PubMed1995

Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations.

Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2-39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovudine-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.

Adult↗

PubMed2003

Acrolein inhibits NADH-linked mitochondrial enzyme activity: implications for Alzheimer's disease.

In Alzheimer's disease (AD) brain increased lipid peroxidation and decreased energy utilization are found. Mitochondria membranes contain a significant amount of arachidonic and linoleic acids, precursors of lipid peroxidation products, 4-hydroxynonenal (HNE) and 2-propen-1-al (acrolein), that are extremely reactive. Both alkenals are increased in AD brain. In this study, we examined the effects of nanomolar levels of acrolein on the activities of pyruvate dehydrogenase (PDH) and Alpha-ketoglutarate dehydrogenase (KGDH), both reduced nicotinamide adenine dinucleotide (NADH)-linked mitochondrial enzymes. Acrolein decreased PDH and KGDH activities significantly in a dose-dependent manner. Using high performance liquid chromatography coupled to mass spectrometry (HPLC-MS), acrolein was found to bind lipoic acid, a component in both the PDH and KGDH complexes, most likely explaining the loss of enzyme activity. Acrolein also interacted with oxidized nicotinamide adenine dinucleotide (NAD(+)) in such a way as to decrease the production of NADH. Acrolein, which is increased in AD brain, may be partially responsible for the dysfunction of mitochondria and loss of energy found in AD brain by inhibition of PDH and KGDH activities, potentially contributing to the neurodegeneration in this disorder.

Acrolein↗

PubMed1994

Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage.

The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA-depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibers with "ragged-red"-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers). Because dysfunctioning muscle mitochondria may lead to defects of beta-oxidation of fatty acids, we examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. Six patients with no AZT fibers had normal endomyofibrillar lipid deposits and muscle carnitine levels; 7 patients with fewer than 5 AZT fibers per field had a mild (+) to moderate (++) increase in lipid droplets, and reduced muscle carnitine levels (3 patients); and 8 patients with more than 5 AZT fibers had severe muscle changes, a ++ to marked ( ) increase in lipid droplets, and reduced muscle carnitine levels (6 patients). Serial sections showed lipid globules often within "cracks" or vacuoles of the abnormal muscle fibers. We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibers owing to poor utilization of long-chain fatty acids, (2) reduction of muscle carnitine levels probably due to decreased carnitine uptake by the muscle, and (3) depletion of energy stores within the muscle fibers. The findings may have potential therapeutic implications in the treatment of AZT-induced myopathic symptoms using oral carnitine supplementation.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Extensive tissue oxygenation associated with mitochondrial DNA mutations.

Extensive tissue oxygenation in the mitochondrial myopathy patients caused by the mitochondrial DNA mutations was first demonstrated noninvasively by a tissue oxymeter measuring near infrared light. The extent of oxygenation of the tissue due to dysfunction of mitochondria correlated with the seriousness of mitochondrial DNA mutations resulting in defects in oxidative phosphorylation system, and causing suppressed oxygen utilization. Such oxygen stress furthers mitochondrial DNA mutations during the progressive course of the disease. This noninvasive diagnosis will find useful application in the diagnosis and management of patients of advanced age.

Adult↗

PubMed1990

Expression in Saccharomyces cerevisiae of a gene associated with cytoplasmic male sterility from maize: respiratory dysfunction and uncoupling of yeast mitochondria.

We asked whether the mitochondrial T-urf13 gene, associated with the male sterility phenotype of T cytoplasm in maize, can be expressed in Saccharomyces cerevisiae and whether this expression can mimic the effects observed in maize. We introduced the universal code equivalent of the T-urf13 gene into the S. cerevisiae nucleus by transformation and directed its translation product into mitochondria by means of a fusion with the targeting presequence from Neurospora crassa AT-Pase subunit 9. We show that expression of the universal code equivalent of the T-urf13 gene in the yeast nucleus does indeed mimic its effects in maize: respiratory growth of yeast is inhibited, respiration-deficient cytoplasmic mutants accumulate and NADH oxidation of isolated mitochondria is uncoupled. All these effects are observed only if the mitochondrial targeting peptide and methomyl or HmT toxin are present.

Chimera↗

PubMed2000

Mitochondrial defects and hearing loss.

The techniques of human molecular genetics have been rapidly applied to the study of hearing loss. These studies have implicated more than 60 loci as causes of nonsyndromic hearing loss. Mutations at more than a dozen nuclear genes have been demonstrated to cause hearing loss, and these have been covered in recent reviews. However, a perhaps unexpected feature of the molecular characterization of human hearing loss has been the occurrence of mutations in the mitochondrial DNA (mtDNA). The importance of mitochondrial function in hearing is emphasized by the recent discovery of mutations in a nuclear-encoded mitochondrial protein which results in hearing loss. This article reviews the current status of our knowledge of mtDNA mutations that have been shown to cause hearing loss, and the suggestion of potential molecular, cellular and tissue-specific pathophysiological mechanisms by which dysfunction of mitochondria may lead to a loss of hearing.

Aminoglycosides↗

PubMed2002

Lipid peroxidation and cell death mechanisms in pulmonary epithelial cells induced by peroxynitrite and nitric oxide.

Nitric oxide (NO) is an environmental pollutant found in smog and cigarette smoke. Recently, NO has been discovered to act as a molecular messenger, mediating various physiological functions. However, when an excess of NO is present, cytotoxic and mutagenic effects can also be induced. The reaction of NO with superoxide results in the formation of peroxynitrite (ONOO(-)), which decomposes into the hydroxyl radical and nitrogen dioxide. Both of them are potent oxidant species that may initiate and propagate lipid peroxidation. In the present study, we examined the effects of NO and ONOO(-) on the induction of lipid peroxidation and cell death mechanisms in rats and in A549 pulmonary epithelial cells. The results showed that ONOO(-) is able to induce lipid peroxidation in pulmonary epithelial cells in a dose-dependent manner. 8-Epi-prostaglandin F(2)(alpha) can serve as a good biomarker of lipid peroxidation both in vitro and in vivo. Postmitotic apoptosis was found in A549 cells exposed to NO, whereas ONOO(-) induced cell death more characteristic of necrosis than apoptosis. Apoptosis that occurred in cells may be related to the dysfunction of mitochondria, the release of cytochrome c into cytosol, and the activation of caspase-9. The relationship between caspase activation and the cleavage of other death substrates during postmitotic apoptosis in A549 cells needs further investigation.

Animals↗

PubMed1997

Alloplasmic wheats with Aegilops crassa cytoplasm which express photoperiod-sensitive homeotic transformations of anthers, show alterations in mitochondrial DNA structure and transcription.

Alloplasmic wheat. Triticum aestivum cv. Norin 26, with Aegilops crassa cytoplasm, shows photoperiod-sensitive cytoplasmic male sterility (PCMS). This alloplasmic line expresses pistillody of anthers only when grown in long-day conditions (> 15 h light). To assess the molecular basis of the PCMS, we carried out Southern and Northern hybridization analyses on mitochondrial DNAs and RNAs isolated from seedlings of alloplasmic lines showing various PCMS phenotypes using probes for twelve mitochondrial genes. All RFLP patterns of mitochondrial DNA from alloplasmic lines greatly differed from those of common wheat, and were slightly changed from those of the parental species, i.e., Ae. crassa. This indicates that nuclear substitutions between related plant species induce structural alterations in the mitochondrial genome. Furthermore, RFLP patterns of (cr)-N61 and FR-mutant probed with coxIII and orf25 were identical with each other, but different from those of the other alloplasmic lines, indicating that the nuclei of N61 and FR-mutant harbor some gene(s) that induces structural alterations of the mitochondrial genome in the coxIII and orf25 regions. The transcription patterns of atp6 and cob in Ae. crassa type were different from those of T. aestivum type. Furthermore, the orf25 transcript in alloplasmic wheats was about 300 nucleotides longer than that of euplasmic lines, including the Ae. crassa pure line, suggesting that transcription patterns of orf25 are associated with recovery from the PCMS phenomenon. These data clearly show the mutual cross-talk between the nuclear genome and chondriome. These observations raise the possibility that the dysfunction of mitochondria caused by the failure of a cooperative control of mitochondrial gene(s) expression influences the pathway of flower morphogenesis, especially in the process that determines organ identity.

Blotting, Northern↗

PubMed2005

Different adaptive traits to cold exposure in young senescence-accelerated mice.

A reduced adaptation to cold is a prominent feature in aged mammals, including humans. The accelerated senescence-prone strain of mice (SAMP) has been studied as an animal model for several age-associated disorders and in the acceleration of senescence. Recent studies revealed that SAMP strains have dysfunctional hyperactive mitochondria and are under a higher oxidative stress status from a young age. To investigate whether young SAMP mice show impaired cold adaptation abilities, we performed cold-exposure experiments. There were no strain differences in baseline body temperature and lowest reached temperature during cold exposure. SAMP1 mice took longer times to reach their lowest temperature in comparison to SAMR1 mice. SAMR1 mice showed an elevation in temperature following cold exposure, whereas SAMP1 mice did not. Behavioral observations demonstrated that SAMP1 mice moved more actively than SAMR1 during cold exposure. However, mRNA levels of uncoupling protein 1 (UCP1), a heat generating protein, as well as plasma norepinephrine levels, were higher in SAMP1 than in SAMR1 mice. This newly found physiological phenotype in SAMP1 mice provides us with a tool to clarify the genetic mechanism which accelerates the senescence process and helps us develop medical means which will bring mankind to a healthy old age.

Adaptation, Physiological↗

PubMed2005

Quantitative analysis of brain NADH in the presence of hemoglobin using microfiber spectrofluorometry: a pre-calibration approach.

Dysfunction of mitochondria links a variety of central nervous system disorders and other neurodegenerative diseases. The primary respiratory chain substrate reduced-form nicotinamide adenine dinucleotide (NADH) is an important regulator of respiratory chain function in mitochondria and, because of its fluorescent properties, has been used to assess mitochondrial pathophysiology in cells and tissues. However, assessment of changes in tissue NADH has been limited to qualitative analysis primarily because hemoglobin (Hb) interferes with NADH fluorescence measurements by absorbing both excitation and emission light. This report presents a computer-assisted approach to estimate tissue NADH and Hb concentrations quantitatively at the same time. The method is based on a two-dimensionally interpolated database model that is calibrated by fluorescence emission spectra with known-value standard chemical solutions. Quantitative concentrations for NADH and Hb can be determined by the corresponding known-value spectral data that have the minimum error to the sample spectrum obtained from an experiment. Repeatability and reliability tests are also presented in this report. Results demonstrate that this method can feasibly quantify the NADH content regardless of the Hb background in living hippocampal cells during hypoxia, suggesting that it has the potential to be applied to in vivo experiments in the future.

Animals↗