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At least 19 recordsLinked to original sources
PubMed2002

An immunocytochemical approach to detection of mitochondrial disorders.

Mitochondrial disorders can lead to a confusing array of symptoms, which frequently makes a diagnosis difficult. Traditional approaches to such diagnoses are based on enzyme activity assays, with further characterization provided by genetic analysis. However, these methods require relatively large sample sizes, are time-consuming, labor-intensive, and show variability between laboratories. Here, we report an immunocytochemical test that makes use of monoclonal antibodies to subunits from each of the oxidative phosphorylation complexes and pyruvate dehydrogenase to aid in the detection of mitochondrial disorders. It can be completed and data analyzed in less than 4 hr. We have used this test to study fibroblast cultures from patients with mitochondrial disorders arising from both mitochondrial DNA and nuclear DNA defects. We have also examined cases of Leigh syndrome arising from different genetic causes. We show that patients can be categorized on the basis of which complexes are affected and whether or not the defect being studied shows a mosaic distribution, an indicator of whether the causal mutation(s) is/are in the mitochondrial or nuclear genome. Immunocytochemical analysis as described here should be considered as an initial screen for mitochondrial disorders by which to direct (and limit) the subsequent enzymatic and genetic tests required to make an unambiguous diagnosis.

Cell Line↗
PubMed2004

New approaches to the treatment of mitochondrial disorders.

Mitochondrial disorders are among the most common inherited metabolic diseases and the issue of treatment arises on a regular basis. There is no established treatment for mitochondrial disorders and current management is largely supportive, but recent advances in our understanding of the pathophysiology provide hope for novel treatments. Patients with mitochondrial myopathy due to mutations of mitochondrial DNA (mtDNA) may benefit from treatments that move normal mitochondrial genomes from the muscle satellite cells into skeletal muscle, but there are concerns about the long-term effects of this approach. A greater understanding of the pathophysiology of a number of nuclear genetic mitochondrial disorders suggests new avenues for treatment (such as copper-histidine in children with SCO2 gene mutations, and strategies modifying intra-mitochondrial nucleoside pools in the various disorders of mtDNA maintenance). A number of different strategies are also being explored at the molecular level, including the use of antigenomic molecules to mutated mtDNA and the allotropic expression of mutated mtDNA genes within the cell nucleus. Nuclear transfer techniques also provide hope for women at risk of transmitting pathogenic mtDNA mutations.

DNA, Mitochondrial↗
PubMed1992

Clinical aspects of mitochondrial disorders.

Mitochondrial disorders have long been regarded as neuromuscular diseases only. In fact, owing to the ubiquitous nature of the oxidative phosphorylation, a broad spectrum of clinical features should be expected in mitochondrial disorders. Here, we present eight puzzling observations which give support to the view that a disorder of oxidative phosphorylation can give rise to any symptom in any organ or tissue with any apparent mode of inheritance. Consequently, we suggest giving consideration to the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and a rapidly progressive course involving seemingly unrelated organs. Determination of lactate/pyruvate and ketone body molar ratios in plasma can help to select patients at risk for this condition.

Child, Preschool↗
PubMed1998

Mitochondrial disorders.

Mitochondrial respiration, the most efficient metabolic pathway devoted to energy production, is at the crosspoint of 2 quite different genetic systems, the nuclear genome and the mitochondrial genome (mitochondrial DNA, mtDNA). The latter encodes a few essential components of the mitochondrial respiratory chain and has unique molecular and genetic properties that account for some of the peculiar features of mitochondrial disorders. However, the perpetuation, propagation, and expression of mtDNA, the majority of the subunits of the respiratory complexes, as well as a number of genes involved in their assembly and turnover, are contained in the nuclear genome. Although mitochondrial disorders have been known for more than 30 years, a major breakthrough in their understanding has come much later, with the discovery of an impressive, ever-increasing number of mutations of mitochondrial DNA. Partial deletions or duplications of mtDNA, or maternally inherited point mutations, have been associated with well-defined clinical syndromes. However, phenotypes transmitted as mendelian traits have also been identified. These include clinical entities defined on the basis of specific biochemical defects, and also a few autosomal dominant or recessive syndromes associated with multiple deletions or tissue-specific depletion of mtDNA. Given the complexity of mitochondrial genetics and biochemistry, the clinical manifestations of mitochondrial disorders are extremely heterogenous. They range from lesions of single tissues or structures, such as the optic nerve in Leber hereditary optic neuropathy or the cochlea in maternally inherited nonsyndromic deafness, to more widespread lesions including myopathies, encephalomyopathies, cardiopathies, or complex multisystem syndromes. The recent advances in genetic studies provide both diagnostic tools and new pathogenetic insights in this rapidly expanding area of human pathology.

DNA, Mitochondrial↗
PubMed1998

[Molecular diagnosis of mitochondrial disorders].

Mitochondrial disorders are caused by either nuclear or mitochondrial DNA abnormalities. The latter but not the former can be examined as a means of diagnosis at present. The peculiarities and problems of the mtDNA test depend strongly on the characteristics of mtDNA itself, such as the multiplicity in number, vulnerability to mutation, and maternal transmission. The mtDNA abnormalities observed in patients with mitochondrial disorders indicate heteroplasmy, tissue/cell specificity, and threshold effects. It should be stressed that the presence of mutant mtDNA in an individual does not mean that he or she is ill. The problems of the mtDNA test could be solved if the genotype-phenotype relationship is farther elucidated in the future study.

DNA, Mitochondrial↗
PubMed2002

Mitochondrial disorders.

Mitochondrial disorders associated with defects in the respiratory chain can be attributable to mutations in the mitochondrial genome (mitochondrial DNA) or the nuclear genome (nuclear DNA). Because the brain is highly dependent on oxidative metabolism, encephalopathy is a common presentation, and epilepsy is a clinical hallmark of many of these conditions. Although most mutations in mitochondrial DNA do not present in infancy, a few mutations in the adenosine triphosphatase gene cause maternally inherited Leigh disease and infantile epilepsy. Early-onset epilepsy is more commonly associated with defects of nuclear genes encoding subunits of respiratory chain complexes or proteins needed for the correct assembly and functioning of the complexes. These defects generally cause autosomal recessive Leigh disease. In this review, the frequency and types of epilepsy (particularly early-onset seizures) are compared according to a genetic classification of the mitochondrial disorders.

Cell Nucleus↗
PubMed2003

Nutritional cofactor treatment in mitochondrial disorders.

Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5'-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented.

Adenosine Triphosphate↗
PubMed2003

Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject.

DNA, Mitochondrial↗
PubMed1997

Introduction of plasmid DNA into isolated mitochondria by electroporation. A novel approach toward gene correction for mitochondrial disorders.

Mitochondrial disorders are a large group of phenotypically heterogeneous diseases. An understanding of their molecular basis would benefit greatly from the ability to manipulate the mitochondrial genome and/or to introduce functional exogenous DNA into mitochondria. As a first step toward this approach, we have used electroporation to introduce a 7.2-kilobase plasmid DNA into isolated functional mitochondria. Transfer of the DNA at field strengths between 8 and 20 kV/cm was investigated by Southern blot analysis. Maximal plasmid internalization was achieved at a field strength of 14 kV/cm. The functional integrity of the mitochondria after electroporation was verified by enzymatic assays of specific mitochondrial marker enzymes and by measuring respiratory control. At field strengths above 12 kV/cm, an increasing mitochondrial destruction was observed. 12 kV/cm was found to be optimal for the most efficient plasmid internalization while still retaining the functional integrity of the mitochondria. At this field strength, about half of the internalized plasmid was found in the inner membrane or mitochondrial matrix, as determined by immunoelectron microscopy and Southern blot analysis of electroporated mitochondria treated with digitonin. We estimate that on average one plasmid molecule/mitochondrion reaches the matrix or inner membrane.

Animals↗
PubMed1998

Towards gene therapy of mitochondrial disorders.

Mitochondrial disorders are characterized by protein deficiencies affecting the structure and function of mitochondria. The protein deficiencies are caused by mutations either in a nuclear gene or in the mitochondrial genome. Most current approaches to gene therapy of mitochondrial diseases aim at expression of the corrective gene sequence by nuclear/cytoplasmic expression. However, the mitochondrial genome and its autonomous expression system offer the potential of an alternative gene therapy strategy: the introduction of nuclear gene sequences into the mitochondrial genome and their expression by the mitochondrial gene expression system. In addition to its potential for gene therapy, the introduction and expression of an exogenous gene in mitochondria would provide an invaluable tool towards the understanding of mitochondrial genome expression and its regulation.

Animals↗
PubMed2005

Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders.

Mitochondrial disorder is characteristic of many myocardial injuries such as endotoxemia, shock, acidosis, ischemia/reperfusion, and others. The goal of possible therapy is to increase ATP production. Derivatives of vitamins K may be a potent electron carrier between various mitochondrial electron-donating and electron-accepting enzyme complexes. We aimed to test the possibility that menadione or its water-soluble derivative AK-135, the newly synthesized analogues of vitamin K1--N-derivatives of 2-methyl-3-aminomethyl 1.4-naphthoquinone, would reduce cardiomyocyte damage after hypoxia or mitochondrial respiratory chain inhibition in culture. Menadione, and more effectively, AK-135, restored the electron flow in defective respiratory chain (hypoxia or rotenone) systems. As was shown in this study, 3 microM of AK-135 restored ATP production after blockade of electron flow through mitochondrial complex I with 5 microM rotenone up to 13.18+/-1.56 vs. 3.21+/-1.12 nmol/mg protein in cells treated with rotenone only. In cultures pretreated with 4 microM dicumarol (DT-diaphorase inhibitor), the protective effect of AK-135 and menadione was abolished completely (1.67+/-1.43 and 2.97+/-0.57 nmol/mg protein, respectively). Inhibition of mitochondrial oxidative phosphorylation caused an increase in intracellular Ca(2+) levels. Here we have demonstrated restoration of calcium oscillations and cardiomyocyte contractility by menadione and its derivative after blockade of NADH: ubiquinone oxidoreductase with rotenone, and decrease of Ca(2+) overloading during hypoxia.

Adenosine Triphosphate↗
PubMed2007

Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.

Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1987

Therapy of mitochondrial disorders.

Mitochondrial disorders, namely defects of fatty acid oxidation, defects of pyruvate metabolism and defects of the respiratory chain are heterogenous in clinical picture and in response to therapeutic attempts. Defects of fatty acid metabolism are amenable to therapy by dietary means, carnitine substitution and in some cases with vitamins. Defects in pyruvate metabolism do not respond to therapy except in some special cases. Therapeutic attempts include dietary measures, vitamins as coenzyme precursors. Defects in the respiratory chain appear to respond to treatment only in exceptional cases. Evaluation of treatment effects appears to be singularly difficult. General measures that can be of benefit to different defects are discussed.

Carnitine↗
PubMed1991

Audiologic findings in a family with mitochondrial disorder.

Mitochondrial disorder is an inborn error of metabolism affecting the cellular respiratory chain. Defective energy production leads to a wide variety of clinical manifestations (ataxia, epilepsy, dementia, myopathy, polyneuropathy, retinal pigment anomalies, and cardiomyopathy with conduction anomalies). Hearing loss is a regular feature and is often the first clinical symptom. Audiologic data from 26 members of a family in three generations is presented. One of these patients was examined for the biochemical error. Respiratory study of muscle biopsy revealed a mild defect in the NADH-ubiquinone oxidoreductase step of the oxidative phosphorylation (complex I). The content of cytochrome aa3 (complex IV) was also reduced. Adult onset sensorineural hearing loss starting in the high frequency region progresses with a fairly constant speed in this family. A cochlear type of hearing loss is found in the less pronounced cases. Advanced cases present features of retrocochlear affection with decreasing speech recognition, elevated acoustic reflex thresholds, and increased ABR latency with derangement of potentials. Caloric sensitivity was unaffected.

Adolescent↗
PubMed2006

Measurement of ATP production in mitochondrial disorders.

Mitochondrial diseases are a heterogeneous group of disorders caused by mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial disease leads to impaired respiratory chain function and reduced ATP production. The aim of this study was to compare disturbances in mitochondrial function by measuring ATP synthesis in fibroblasts derived from patients with nDNA and mtDNA defects. Skin fibroblasts derived from 22 patients with either nDNA-related disorders (n = 8) or mtDNA-related disorders (n = 14) were analysed. ATP synthesis was markedly decreased in fibroblasts derived from patients with nDNA-related disorders but only variably so in patients with mtDNA mutations. In fibroblasts with the MELAS 3243A > G mutation, ATP synthesis correlated with mutant load. We believe that the observed differences in ATP production between cell lines derived from patients with nDNA-related disorders and mtDNA-related disorders may help in the assessment of patients with undiagnosed mitochondrial disease. The clinical comparisons observed in patients with nDNA- and mtDNA-related disorders may be explained by differences in the disturbance of ATP synthesis measured in the two conditions.

Adenosine Triphosphate↗
PubMed2004

Thymidine phosphorylase deficiency causes MNGIE: an autosomal recessive mitochondrial disorder.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases.

Blotting, Southern↗
PubMed2004

Neuroimaging of mitochondrial disorders.

Mitochondrial disease is frequently a multisystem disorder which often involves the central nervous system. Imaging finding although diverse are characterized by focal lesions with T2 hyperintensity, which may be most evident on FLAIR imaging and often progress to atrophy. Deep brain structures including brainstem and basal ganglia structures are particularly vulnerable though white matter and cortex may also be involved. In this paper we describe in detail the imaging features of the spectrum of mitochondrial diseases and suggest a scoring technique for recording severity and extent of brain involvement. Although there is overlap between the imaging features of disease phenotypes, magnetic resonance imaging may be useful in supporting the clinical diagnosis. There is little correlation between molecular defect and imaging findings with some noticeable exceptions such as the MELAS syndrome.

Journal Article↗
PubMed1998

Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders.

Mitochondrial transmembrane carrier deficiencies are a recently discovered group of disorders, belonging to the so-called mitochondriocytopathies. We examined the human tissue distribution of carriers which are involved in the process of oxidative phosphorylation (adenine nucleotide translocator, phosphate carrier, and voltage-dependent anion channel) and some mitochondrial substrate carriers (2-oxoglutarate carrier, carnitine-acylcarnitine carrier, and citrate carrier). The tissue distribution on mRNA level of mitochondrial transport proteins appears to be roughly in correlation with the dependence of these tissues on mitochondrial energy production capacity. In general the main mRNA expression of carriers involved in mitochondrial energy metabolism occurs in skeletal muscle and heart. Expression in liver and pancreas differs between carriers. Expression in brain, placenta, lung, and kidney is lower than in the other tissues. Western and Northern blotting experiments show a comparable HVDAC1 protein and mRNA distribution for the tested tissues. Patient's studies showed that cultured skin fibroblasts may not be a reliable alternative for skeletal muscle in screening for human mitochondrial carrier defects.

Adenine Nucleotides↗