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At least 19 recordsLinked to original sources
PubMed2002

Noninvasive, in vivo approaches to evaluating behavior and exercise physiology in mouse models of mitochondrial disease.

Mitochondrial diseases are a clinically heterogeneous group of disorders related to dysfunction of various components of oxidative metabolism. Common manifestations of these diseases include encephalopathy, skeletal myopathy, and cardiomyopathy, but essentially any tissue can be affected. To understand better the pathogenesis of mitochondrial disease and to potentially evaluate novel therapies, several mouse models have been reported in the literature over the past few years. In assessing genetically altered mice as potential models of human mitochondrial disease, careful behavioral and physiologic analyses are essential components of the overall phenotypic characterization. Noninvasive, in vivo approaches are useful because they assess end-organ and multiorgan function in a whole-organism context, as well as permit serial measurements of individual animals over time. This review presents various behavioral and exercise physiology protocols that can be used for the evaluation of potential mouse models of human mitochondrial disorders.

Animals↗
PubMed2003

Transcription factors c-Jun/activator protein-1 and nuclear factor-kappa B in oxidative stress response in mitochondrial diseases.

Mitochondrial dysfunction leads to oxygen free radical (ROS) generation with consequent oxidative stress and cellular damage. Recently, activation of the cellular antioxidant system and apoptosis were demonstrated in skeletal muscle fibres from patients with mitochondrial diseases, but the underlying mechanisms remain unknown. Hydrogen peroxide, a by-product of ROS generation, is a chemical inducer of gene expression able to activate apoptosis and to promote the antioxidant response through the activation of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) transcription factor. Using immunohistochemistry and confocal microscopy, we evaluated the expression of NF-kappaB and AP-1 in muscle biopsies from patients with mitochondrial disease. In addition, we examined the expression of factors involved in their activation, such as NF-kappaB inducing kinase (NIK) and phosphorylated Jun-N-terminal kinase (p-JNK). Most fibres with respiratory chain dysfunction displayed nuclear staining for activated c-Jun/AP-1, but not for NF-kappaB. The same fibres reacted for p-JNK. Only some ragged red fibres immunoreacted for NIK. These data suggest that AP-1 is involved in the oxidative stress response in muscle fibres from patients with mitochondrial disease.

Humans↗
PubMedDate not supplied

[Mitochondrial diseases].

Mitochondrial disease are a heterogeneous group, combining multiple symptoms resulting from defects in various organs. Thus identification of a particular mitochondrial disease due to clinical symptoms is not possible. However, simple biochemical tests can provide guiding and reliable results quickly. We present a classification of the mitochondrial diseases, describing important clinical symptoms and explaining a diagnostic plan to identify defects of biochemical mitochondrial pathways.

Abnormalities, Multiple↗
PubMed1989

Mitochondrial diseases.

Mitochondrial diseases, and particularly mitochondrial myopathies or encephalomyopathies, have drawn increasing attention in the past decade. Initially defined by morphologic changes in muscle ("ragged red fibers" and ultrastructural abnormalities of mitochondria), mitochondrial encephalomyopathies can now be classified according to biochemical defects involving: (1) mitochondrial transport; (2) substrate oxidation; (3) Krebs cycle; (4) respiratory chain; and (5) oxidation-phosphorylation coupling. For each biochemical group of disorders, the authors describe clinical presentations and biochemical findings. These disorders are especially interesting from the genetic point of view because mitochondria have their own DNA (mtDNA), which encodes 13 polypeptides, all of them subunits of respiratory chain complexes. Other mitochondrial proteins are encoded by nuclear DNA, synthesized in the cytoplasm, and imported into the mitochondria by a complex mechanism. Because mtDNA is inherited strictly by maternal, cytoplasmic inheritance, mitochondrial diseases can be transmitted by Mendelian or by non-Mendelian, maternal inheritance, as illustrated by human pathology.

Brain Diseases, Metabolic↗
PubMed1996

Variations of muscle mitochondrial creatine kinase activity in mitochondrial diseases.

Mitochondrial creatine kinase (mtCK) activity has been measured in the mitochondria isolated from the muscle of 69 patients suspected of mitochondrial diseases. The isolated mitochondria did not contain significant amounts of the muscle isoform of creatine kinase, as checked by an immunoassay performed after electrophoretic separation of the various isoforms. Hence, the enzyme assay reliably represented the mtCK activity. Therefore, a simple measurement of CK activity in isolated mitochondria permitted the measurement of mtCK activity. An absence of mtCK activity in muscle was never observed. The lowest activities were not associated to defined mitochondrial diseases linked to defects of respiratory chain complexes or to defects of citric cycle enzymes. On the contrary, mtCK activity was significantly increased in the muscle of patients exhibiting ragged red fibers. This increase was generally associated to an increase of citrate synthase activity. Since ragged-red fibers and elevated mtCK activities were generally not found in children younger than 3 years, even in cases of characteristic oxidative phosphorylation deficiency, it is suggested that the increase in mtCK activity as well as the appearance of ragged-red fibers are not the first events which occur during the evolution of mitochondrial diseases but would rather be long-term secondary processes which slowly develop in deficient mitochondria.

Adolescent↗
PubMed2006

Multimodal evoked potentials in three siblings with mitochondrial disease.

Mitochondrial diseases are heterogeneous disorders affecting multiple systems. Here, we presented the findings of multimodal evoked potential (EP) studies of three siblings with a specific A8344G mutation of mitochondrial DNA. One of them had DM and another two had a history of encephalopathy. Visual EPs were abnormal in one patient and motor, somatosensory and brainstem auditory EPs were observed in all three patients. Our EP studies showed that the A8344G mutation of mitochondrial DNA involved multiple levels of the central nervous system even though there were no correlated symptoms. Therefore EP is an adjunct of methods to detect the functional disturbance and to screen the distribution of the involvement of the nervous system in mitochondrial diseases.

Adult↗
PubMed2002

Mitochondrial diseases.

Mitochondrial disorders are caused by deficient respiratory chain function, resulting in a complex series of pathophysiological events. Genetic counselling is complicated because the respiratory chain subunits are encoded by both nuclear and mitochondrial DNA genes. Only a minority of the nuclear genes involved in mitochondrial function have been identified, and even fewer are associated with human mitochondrial disease. Mutations in mitochondrial DNA are particularly challenging because of the complexities of mitochondrial genetics: the mitochondrial DNA is strictly maternally inherited; there are 10(3)-10(4) copies of mitochondrial DNA in somatic cells; affected individuals often have a mixture of normal and mutated mitochondrial DNA (mitochondrial DNA heteroplasmy), the level of mutated mitochondrial DNA (the mitochondrial DNA mutation load) may vary widely between different maternally related individuals, between tissues and with time; a particular minimal threshold of mutated mitochondrial DNA is required to impair respiratory chain function; and there is not always a good correlation between mutant load and phenotype.

DNA, Mitochondrial↗
PubMed1998

Anaesthesia and mitochondrial disease.

Mitochondrial diseases, or encephalomyopathies, are an uncommon, heterogeneous group of disorders with variable clinical course and presentation. Many of these patients present for surgery, or undergo anaesthesia in the course of investigation of their illness. Unfortunately, little information exists on their management in anaesthetic texts and the literature. We report on the anaesthetic management of a paediatric patient with mitochondrial disease, and briefly discuss the pathophysiology and anaesthetic implications of these disorders.

Anesthesia, Inhalation↗
PubMed2022

Current advances in gene therapy of mitochondrial diseases.

Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.

Humans↗
PubMed2000

[Nephrologic manifestations of mitochondrial diseases].

Mitochondrial diseases, rated as rarities in paediatrics and neurology, become more and more often diagnosed in various body systems. In nephrology, mitochondrial defects play an important role in the pathogeny of tubular syndromes, interstitial nephritis, focal and segmental glomerulosclerosis, and probably also some other diseases. Review is aimed to point out such defects and to form conditions for their diagnosis and therapy.

Humans↗
PubMed2001

Diagnosis and treatment of childhood mitochondrial diseases.

Mitochondrial cytopathies are caused by genetic alterations of nuclear- or mitochondrial-encoded genes involved in the synthesis of subunits of the electron transport chain. Mutations of mitochondrial DNA are associated with a wide range of clinical presentations [1-4]. The ubiquitous nature of mitochondria and the role of the mitochondria in cellular metabolism result in the potential for any tissue in the body to be affected [5-7,8..,9]. Although some children with mitochondrial disease present with life-threatening lactic acidosis in the newborn period, the majority of children come to clinical attention for nonspecific problems, including failure to thrive, developmental delay, seizures, hypotonia, and loss of developmental milestones. The diagnosis of these disorders is made through careful clinical evaluation, coupled with biochemical, morphologic, and molecular biologic techniques. Genetic counseling is difficult due to unique aspects of mitochondrial genetics. Despite advances in our understanding of mitochondrial biochemistry and genetics, treatment options remain limited.

Biomarkers↗
PubMed1994

Mitochondrial diseases.

Mitochondrial diseases are heterogeneous and characterized by a primary defect of the mitochondrial energy output. Genetic defects of mitochondrial energy enzymes may be due to either nuclear DNA gene mutations or mitochondrial DNA (mtDNA) mutations. Among hereditary defects of nuclear-encoded mitochondrial enzymes, carnitine palmitoyltransferase II (CPT-II) deficiency and pyruvate dehydrogenase complex (PDHC) deficiency are of major interest to the neurologist. Several mutations in the CPT-II gene as well as in the X-linked E1 alpha subunit gene of PDHC have been reported and associated with different clinical phenotypes. mtDNA-related syndromes include mitochondrial encephalomyopathies (e.g. MELAS, MERRF, NARP, MIMyCa, etc.), 'pure' encephalopathies (e.g. LHON) and a few syndromes involving only non-neurological systems (e.g. Pearson's pancreas-bone marrow syndrome or diabetes mellitus). Three kinds of molecular lesions have been identified in mtDNA-related disorders: point mutations of protein-encoding mtDNA genes (mit- mutations), point mutations of mtDNA-tRNA genes (syn- mutations) and large-scale rearrangements of mtDNA (rho- mutations). Point mutations (mit- and syn+) are usually maternally inherited, while single large-scale mtDNA rearrangements are usually sporadic. Furthermore, mendelian traits leading to either qualitative or quantitative abnormalities of mtDNA (i.e. multiple mtDNA deletions and tissue-specific mtDNA depletion, respectively) are the first examples of genetic dysfunction of nuclear-mitochondrial communication. In most cases, the molecular detection of the known defects of mtDNA can be carried out by non-invasive techniques, thus making it an easy and relatively inexpensive procedure in the differential diagnosis of the mitochondrial disorders, a rapidly expanding area of clinical neurology.

DNA, Mitochondrial↗
PubMed1996

Clinical spectrum of mitochondrial diseases.

Mitochondrial diseases include myopathies and multisystem disorders. They are characterized by morphologic and biochemical abnormalities of mitochondria. Their genetic characteristics-maternal inheritance, heteroplasmy, mitotic segregation, and threshold effect-are unique. The clinical phenotypes are considerably heterogeneous, but the clinical presentation in many cases is characteristic or suggestive. We review the clinical features of the most prevalent mitochondrial encephalomyopathy syndromes, their molecular genetic basis, isolated clinical symptoms, and uncommon presentations. Molecular genetic diagnosis is available for the common syndromes and has revolutionized their diagnosis. Future therapeutic advances, based on the precise genetic etiology, are anticipated. Mitochondrial dysfunction may be a more frequent pathogenetic mechanism than the prevalence of the classic mitochondrial syndromes would indicate, as there is an association between the accumulation of mitochondrial DNA mutations in postmitotic tissues and neurologic and systemic degenerative diseases.

Animals↗
PubMed2001

Mitochondrial Disease.

Mitochondrial diseases are disorders of energy metabolism that include defects of pyruvate metabolism, Krebs cycle, respiratory chain (RC), and fatty acid oxidation (FAO). Treatment of pyruvate metabolism, Krebs cycle, and RC disorders is, in general, disappointing. Therapeutic approaches consist of electron acceptors, enzyme activators, vitamins, coenzymes, free-radical scavengers, dietary measures, and supportive therapy. These treatment assumptions are based on current understanding of the pathophysiology, on anecdotal clinical reports, and on a few controlled clinical trials, which have not been encouraging. Although it is difficult to perform clinical trials in these conditions due to their rarity and genotypic and phenotypic heterogeneity, there is a great need for well-performed double-blind placebo- controlled clinical trials with comparable groups of patients and with sufficient follow-up periods. Treatment options for FAO disorders are, in general, satisfactory and are mainly based on diet, lifestyle recommendations, and administration of L-carnitine and, in some cases, riboflavin. Special conditions that involve primary deficiencies of L-carnitine, coenzyme Q(10), and cofactor- and vitamin-responsive enzyme defects must be systematically considered, because supplementation with these substances may be curative or produce dramatic improvements. While awaiting more specific therapies for mitochondrial disorders, it is useful to reach a consensus regarding the management of these patients. The expected outcome is a slowing of the disease process and stabilization of the clinical syndrome. More definitive treatments hopefully will follow in the near future.

Journal Article↗
PubMed1993

[Mitochondrial diseases].

Mitochondrial diseases are very complex. Their description, recent but still in progress, makes all classifications risky. In the first part of this article we present the original character of mitochondria, which is due to their functional structure aimed to produce energy, the respiratory chain being fundamental for the phosphorylation/oxidation and ATP production processes. Beside Mendelian transmission, mitochondria have their own DNA which codes for proteins that are few but play an essential role; the nuclear DNA probably has a regulatory effect. For these reasons, explorations of mitochondrial functioning, mainly by morphological, biochemical and genetic techniques, are specific. In the second, clinical part, we analyse the whole range of symptoms and syndromes which includes purely muscular lesions, predominantly nervous lesions and multisystemic lesions. Some syndromes can be individualized on a biochemical basis, whereas other are individualized on a genetic basis involving mainly mutations of mitochondrial DNA. Finally, we merely list lesions the origin of which might be mitochondrial but remains unknown.

Humans↗
PubMed2005

How is mitochondrial biogenesis affected in mitochondrial disease?

Mitochondrial biogenesis occurs when the tissue energy demand is chronically increased to stress the ATP producing capacity of the preexisting mitochondria. In muscle, endurance training is a metabolic stress that is capable of inducing mitochondrial biogenesis, the consequence of which is improved performance during exercise. Expansion of the mitochondrial volume requires the coordinated response of the nuclear and mitochondrial genomes. During acute exercise, the initial signaling events are the perturbations in ATP turnover and calcium (Ca) concentrations caused by the contractile process. These alterations activate signal transduction pathways which target transcription factors involved in gene expression. Nuclear gene products are then posttranslationally imported into mitochondria. One of these, Tfam, is important for the regulation of mitochondrial DNA (mtDNA) gene expression. In muscle, a broad range of mitochondrial-specific diseases due to mutations in nuclear DNA or mtDNA exist, termed mitochondrial myopathies. These mutations result in dysfunctional mitochondrial assembly which ultimately leads to reduced ATP production. Mitochondrial myopathy patients exhibit a variety of compensatory responses which attempt to reconcile this energy deficiency, but the extent and the type of compensatory adaptations are disease-specific. Understanding the role of exercise in mediating these compensatory responses leading to mitochondrial biogenesis could help us in prescribing exercise designed to improve mitochondrial function in patients with mitochondrial myopathies. In addition, numerous other diseases (e.g., neurological disorders, cancer, diabetes, and cardiomyopathies), as well as the aging process, have etiologies or consequences attributed, in part, to mitochondrial dysfunction. Thus, insight gained by investigating the steps involved in exercise-induced mitochondrial biogenesis may help us to understand the underlying basis of these other disease states.

DNA Mutational Analysis↗
PubMed2005

Pulmonary hypertension--a new manifestation of mitochondrial disease.

Mitochondrial respiratory chain (RC) abnormalities in children can present as multiorgan disease, including liver failure, usually within the first year of life. Cardiorespiratory complications have previously been described in association with RC defects; however, to our knowledge no cases of pulmonary hypertension have been described. We discuss two patients with proven mitochondrial RC liver disease who developed severe pulmonary hypertension, one subsequent to cadaveric orthotopic liver transplantation, the second in the neonatal period. It is our contention that pulmonary hypertension should now be included as another potential manifestation of paediatric mitochondrial disease.

Adenosine Triphosphate↗
PubMed2001

Approaches and limitations to gene therapy for mitochondrial diseases.

Mitochondrial dysfunction may be caused by mutations in either the nuclear and/or the mitochondrial genome. Since 1988, mitochondrial DNA mutations have been linked to retinopathies, myopathies, neurodegenerative diseases, and possibly normal aging. Adequate drug therapies for these disorders have yet to be discovered. Therefore, gene therapy must be considered as a possible alternative. In this review, we will discuss the possibilities and the problems associated with gene therapy for mitochondrial disorders.

Animals↗