Mitochondrial Diseases ‐ An Expanding Spectrum of Disorders and Affected Genes

Department of Pediatrics, University of Cologne, Joseph-Stelzmann-Strase, D-50924 Koln, Germany.
Experimental Physiology (Impact Factor: 2.67). 02/2003; 88(1):155-66. DOI: 10.1113/eph8802509
Source: PubMed


Mitochondrial diseases are a heterogeneous group of disorders caused by the impairment of the mitochondrial oxidative phosphorylation system which have been associated with various mutations of the mitochondrial DNA (mtDNA) and nuclear gene mutations. The clinical phenotypes are very diverse and the spectrum is still expanding. This review gives an overview of the principal clinical phenotypes and the molecular genetic basis of mitochondrial disorders identified so far.

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Available from: Wolfram S Kunz, Apr 15, 2014
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    • "In total, there are 18 somatic mutations were detected in the 59 tissue samples under study (Figure 1 and Table S1), and all the somatic mutations occur merely on the terminal branches of phylogenic tree, and no haplotype-shift was observed. With the exception of the RNA-coding genes (including sRNA and tRNA), these somatic mutation sites are dispersed across the entire mtDNA genome, which seems quite different from the mutation spectrum observed in patients with mitochondrial diseases [25], [26]. Specifically, seven mutations locate in the D-loop region, whereas the remaining 11 locate in protein-coding regions. "
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    ABSTRACT: In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients.
    Full-text · Article · Jun 2011 · PLoS ONE
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    • "On the other hand, it was suspected that a considerable portion of the data in the literature are due to various PCR and sequencing artefacts or contamination of the tumor sample by DNA of laboratory members [6]. Mutations of mtDNA can lead to mitochondrial dysfunction and result in a great variety of disorders affecting almost any organ in the body, but most obviously the central nervous and sensory system , skeletal muscle and heart [7], and are now well accepted to contribute to the aging process in general [8]. Therefore, it was also hypothesized that at least the pathogenic mtDNA mutations could have highly relevant functional consequences for tumor biology [3]. "
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    ABSTRACT: In search of tumor-specific mitochondrial DNA (mtDNA) mutations in head and neck squamous cell cancer, we found heteroplasmy in the blood of two individuals, i.e., these individuals carried two alleles of mtDNA. In both cases, the tumor was found to be homoplasmic, i.e., it contained only one of the two mtDNA alleles present in blood. More interestingly, in one case the tumor had acquired the wild-type allele, while in the other case it contained the mutant allele only. Sequencing of the whole 16.5 kb mtDNA showed that the observed heteroplasmic positions in the D-loop region, nucleotides 152 and 16187, respectively, were the only differences between tumor and blood mtDNA genotypes in these individuals. Our findings thus strongly support the hypothesis that accumulation of mtDNA mutations in solid tumors occurs by clonal and random expansion of pre-existing alleles and is not necessary for the metabolic changes generally associated with tumor formation, the Warburg effect.
    Full-text · Article · Mar 2009 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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    • "However, whether and how these findings correspond to the pathogenic mechanisms in the more complex and different architecture of the affected tissues of interest in any one patient and how these consequences are modulated in the complex interplay of whole organism metabolism is anything but clear or straightforward . Still, those different consequences observed on the cellular level are most likely relevant for the tremendous and largely unexplained variability of the clinical consequences of those mutations, e.g. the various clinical phenotypes of patients with mitochondrial disease [9]. "
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    ABSTRACT: Energy-producing pathways, adenine nucleotide levels, oxidative stress response and Ca(2+) homeostasis were investigated in cybrid cells incorporating two pathogenic mitochondrial DNA point mutations, 3243A>G and 3302A>G in tRNA(Leu(UUR)), as well as Rho(0) cells and compared to their parental 143B osteosarcoma cell line. All cells suffering from a severe respiratory chain deficiency were able to proliferate as fast as controls. The major defect in oxidative phosphorylation was efficiently compensated by a rise in anaerobic glycolysis, so that the total ATP production rate was preserved. This enhancement of glycolysis was enabled by a considerable decrease of cellular total adenine nucleotide pools and a concomitant shift in the AMP+ADP/ATP ratios, while the energy charge potential was still in the normal range. Further important consequences were an increased production of superoxide which, however, was neither escorted by major changes in the antioxidative defence systems nor was it leading to substantial oxidative damage. Most interestingly, the lowered mitochondrial membrane potential led to a disturbed intramitochondrial calcium homeostasis, which most likely is a major pathomechanism in mitochondrial diseases.
    Full-text · Article · Aug 2007 · Experimental Cell Research
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