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  • 1
    Electronic Resource
    Electronic Resource
    Intracellular heteroplasmy for disease-associated point mutations in mtDNA: implications for disease expression and evidence for mitotic segregation of heteroplasmic units of mtDNA (1995)
    Springer
    Human genetics 〈Berlin〉 96 (1995), S. 261-268 
    Details
    ISSN: 1432-1203
    Keywords: Mitochondrial DNA ; MELAS ; Leber's hereditary optic neuropathy ; Mitochondrial disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Studies in vitro have shown that a respiratorydeficient phenotype is expressed by cells when the proportion of mtDNA with a disease-associated mutation exceeds a threshold level, but analysis of tissues from patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) have failed to show a consistent relationship between the degree of heteroplasmy and biochemical expression of the defect. One possible explanation for this phenomenon is that there is variation of heteroplasmy between individual cells that is not adequately reflected by the mean heteroplasmy for a tissue. We have confirmed this by study of fibroblast clones from subjects heteroplasmic for the MELAS 3243 (A→ G) mtDNA mutation. Similar observations were made with fibroblast clones derived from two subjects heteroplasmic for the 11778 (G→A) mtDNA mutation of Leber's hereditary optic neuropathy. For the MELAS 3243 mutation, the distribution of mutant mtDNA between different cells was not randomly distributed about the mean, suggesting that selection against cells with high proportions of mutant mtDNA had occurred. To explore the way in which heteroplasmic mtDNA segregates in mitosis we followed the distribution of heteroplasmy between clones over approximately 15 generations. There was either no change or a decrease in the variance of intercellular heteroplasmy for the MELAS 3243 mutation, which is most consistent with segregation of heteroplasmic units of multiple mtDNA molecules in mitosis. After mitochondria from one of the MELAS 3243 fibroblast cultures were transferred to a mitochondrial DNA-free (ρ0) cell line derived from osteosarcoma cells by cytoplast fusion, the mean level and intercellular distribution of heteroplasmy was unchanged. We interpret this as evidence that somatic segregation (rather than nuclear background or cell differentiation state) is the primary determinant of the level of heteroplasmy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00210404
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  • 2
    Electronic Resource
    Electronic Resource
    Excitatory Amino Acid Synthesis in Hypoxic Brain Slices: Does Alanine Act as a Substrate for Glutamate Production in Hypoxia? (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Excitatory amino acids are an important cause of cell death in the hypoxic and ischaemic brain. Neuronal glutamate stores are depleted rapidly in hypoxia, but alanine production rises under such conditions and has been suggested to be a potential precursor of glutamate. To test this hypothesis, we have investigated amino acid metabolism using 13C NMR with superfused guinea pig cortical slices subjected to varying degrees of hypoxia. During severe hypoxia, brain slices metabolising 5 mM [2-13C]pyruvate exported [2-13C]alanine into the superfusion fluid. The metabolic fate of alanine during normoxia and hypoxia was tested by superfusion of brain slices with 10 mM glucose and 2 mM [2-13C, 15N]alanine. Metabolism of exogenous alanine leads to the release of aspartate into the superfusion fluid. The pattern of labelling of aspartate indicated that it was synthesised via the glial-specific enzyme pyruvate carboxylase. 13C-labelled glutamate was produced with both normoxia and hypoxia, but concentrations were 30-fold lower than for labelled aspartate. Thus, although substantial amounts of glutamate are not synthesised from alanine in hypoxia, there is significant production of aspartate, which also may have deleterious effects as an excitatory amino acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71062477.x
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  • 3
    Electronic Resource
    Electronic Resource
    Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology (1999)
    Springer
    Acta neuropathologica 97 (1999), S. 346-354 
    Details
    ISSN: 1432-0533
    Keywords: Key words Cytochrome oxidase ; Neurofibrillary ; tangles ; Amyloid plaques ; Alzheimer’s disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recent reports have suggested that mitochondrial dysfunction may contribute to the progression of the pathology of Alzheimer’s disease (AD). However, both increases and decreases in the activity of cytochrome oxidase have been described in the hippocampi of AD patients. In this study we used immunohistochemistry and quantitative autoradiographic methods to study the expression pattern of two cytochrome oxidase subunit proteins (nuclear-encoded COX IV and mitochondrial-encoded COX I) in the hippocampus in relation to the development of AD-type pathology. We found heterogeneous expression of both COX subunits in AD with an increased expression of both subunit proteins in healthy, non-tangle-bearing, neurones but absence of both subunit proteins in tangle-bearing neurones. Levels of COX IV but not of COX I were related to the amount of hyperphosphorylated tau accumulated in the same hippocampal region but not to the amount of amyloid deposited in sporadic AD. In Down’s syndrome COX I and COX IV were similarly increased in the presence of AD pathology in non-tangle-bearing neurones. However, in these cases levels of enzyme expression were correlated to the amount of amyloid accumulation but not the amount of hyperphosphorylated tau in the hippocampus. We believe that heterogeneity of expression of mitochondrial enzyme proteins between neurones may contribute to the conflicting conclusions in previous reports regarding relative levels of cytochrome oxidase activity in the hippocampus in AD. We hypothesise that the increased mitochondrial enzyme expression in healthy-appearing neurones of AD brains may represent a physiological response to increased functional demand on surviving neurones as a consequence of AD-related neuronal pathology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010050997
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  • 4
    Electronic Resource
    Electronic Resource
    Functional magnetic resonance imaging: Clinical applications and potential (1999)
    Springer
    Journal of inherited metabolic disease 22 (1999), S. 337-352 
    Details
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Demonstration that contrast in magnetic resonance images can be generated based on differences in blood oxygenation has led to an explosion of interest in so-called functional magnetic resonance imaging (FMRI). FMRI can be used to map increases in blood flow that accompany local synaptic activity in the brain. The technique has proved remarkably sensitive and has been used to map a broad range of cognitive, motor and sensory processes in the brain entirely non-invasively. More recently, efforts have been made to extend this technique to the analysis of clinical problems. A major application is for presurgical localization of cerebral functions, e.g. in the surgical treatment of epilepsy. The technique also is beginning to provide information on functional consequences of abnormal brain development. Perhaps most exciting are applications to neurological impairments that are not associated with structural abnormalities, such as learning problems, dyslexia and movement disorders. It is possible that useful applications of FMRI may be found for directly mapping sites of action of CNS-active drugs. Although the extent of the potential clinical applications of this new brain mapping technique is not clear, the widespread availability of MRI scanners suggests that the technique should in some form soon become a routine tool in major neuroradiological centres.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005535102667
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  • 5
    Electronic Resource
    Electronic Resource
    Applications of magnetic resonance spectroscopy to diagnosis and monitoring of mitochondrial disease (1997)
    Springer
    Neurological sciences 18 (1997), S. 341-351 
    Details
    ISSN: 1590-3478
    Keywords: Magnetic resonance spectroscopy ; MRI ; Mitochondrial disease ; Myopathy ; Therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Sommario La risonanza magnetica spettroscopica (MRS) può oggi essere effettuata di routine in apparecchi clinici di risonanza magnetica. Nell'ultima decade essa ha fornito importanti informazioni nella patofisiologia dei disordini mitocondriali. Più recentemente sono state dimostrate le sue possibilità di applicazione nella diagnosi clinica e nel monitoraggio di pazienti neurologici. Nuovi ed interessanti studi suggeriscono che un allenamento attentamente supervisionato in congiunzione con trattamento con dicloroacetato è capace di migliorare i parametri biochimici e la performance di pazienti con miopatie mitocondriali.
    Notes: Abstract Magnetic resonance spectroscopy (MRS) can now be performed on routine high-field clinical magnetic resonance imaging systems. Over the last decade it has provided several useful insights into the pathophysiology of mitochondrial disorders. More recently, the feasibility of applications to clinical diagnosis and monitoring have been demonstrated. Exciting new work suggests that carefully supervised physical conditioning in conjunction with sodium dichloroacetate administration can markedly enhance both biochemical measures of aerobic metabolism and functional performance of patients with mitochondrial myopathies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02048237
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