RESUMEN
A 48-year-old man presented to our lipid clinic with statin intolerance and elevated serum creatine kinase levels, being affected by mitochondrial myopathy because of heteroplasmic mitochondrial DNA missense mutation in MTCO1 gene (m.7671T>A). He had just been treated with a coronary artery bypass 4 years before because of acute coronary syndrome, and he had consistently high levels of both low-density lipoprotein cholesterol and triglycerides. Dyslipidemia was successfully treated using 75 mg of alirocumab subcutaneously every 2 weeks, 10 mg of ezetimibe daily, 2 g of marine omega-3 fatty acids daily, and 145 mg of micronized fenofibrate every 2 days. Although muscle weakness persisted, myalgia did not reoccur and serum creatine kinase levels remained almost stable over the time.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Miopatías Mitocondriales/tratamiento farmacológico , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/patología , Mutación Missense , PronósticoRESUMEN
Restoration of deoxyribonucleic acid in mitochondrial myopathies may occur after a mechanical or chemical injury of striated muscle or by endurance training. Therapies with enzymes, gene therapies, or treatments with substances that stimulate mitochondrial biogenesis are used at the moment. Genesis of mitochondria may also come from myonuclei by releasing the nuclear respiratory factor-1/2 during muscle contractions. Multiplying of myonuclei depends on muscle satellite cell activation. Since the electromyostimulation increase the number of circulating stem cells that may participate in the genesis of new muscle fibers (adding to the deposit of specific stem cells of the muscle), and intermittent hypoxia stimulates the proliferation of muscle satellite cells, we propose to combine the two processes for the treatment of mitochondrial myopathies. Respective combined therapy may be useful for restoring damaged mitochondria by drug side effects.
Asunto(s)
Terapia por Estimulación Eléctrica , Terapia Genética , Hipoxia , Miopatías Mitocondriales/terapia , ADN/metabolismo , Terapia por Estimulación Eléctrica/métodos , Terapia Genética/métodos , Humanos , Mitocondrias/metabolismo , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/patología , Fibras Musculares Esqueléticas/metabolismo , Resultado del TratamientoRESUMEN
Mitochondria are found in all nucleated human cells and perform a variety of essential functions, including the generation of cellular energy. Most of mitochondrial proteins are encoded by the nuclear DNA (nDNA) whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction which leads to a wide range of cellular perturbations including aberrant calcium homeostasis, excessive reactive oxygen species production, dysregulated apoptosis, and insufficient energy generation to meet the needs of various organs, particularly those with high energy demand. Impaired mitochondrial function in various tissues and organs results in the multi-organ manifestations of mitochondrial diseases including epilepsy, intellectual disability, skeletal and cardiac myopathies, hepatopathies, endocrinopathies, and nephropathies. Defects in nDNA genes can be inherited in an autosomal or X-linked manners, whereas, mtDNA is maternally inherited. Mitochondrial diseases can result from mutations of nDNA genes encoding subunits of the electron transport chain complexes or their assembly factors, proteins associated with the mitochondrial import or networking, mitochondrial translation factors, or proteins involved in mtDNA maintenance. MtDNA defects can be either point mutations or rearrangements. The diagnosis of mitochondrial disorders can be challenging in many cases and is based on clinical recognition, biochemical screening, histopathological studies, functional studies, and molecular genetic testing. Currently, there are no satisfactory therapies available for mitochondrial disorders that significantly alter the course of the disease. Therapeutic options include symptomatic treatment, cofactor supplementation, and exercise.
Asunto(s)
Síndrome de Kearns-Sayre/patología , Miopatías Mitocondriales/patología , Animales , Metabolismo Energético , Humanos , Síndrome de Kearns-Sayre/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Miopatías Mitocondriales/genética , Modelos BiológicosRESUMEN
Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.
Asunto(s)
Acidosis Láctica/complicaciones , Acidosis Láctica/terapia , Enfermedad de la Orina de Jarabe de Arce/complicaciones , Enfermedad de la Orina de Jarabe de Arce/terapia , Miopatías Mitocondriales/patología , Miopatías Mitocondriales/terapia , Riboflavina/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Biopsia , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Músculos/patología , Fenotipo , Estabilidad Proteica/efectos de los fármacos , Adulto JovenRESUMEN
Long-chain 3-hydroxylated fatty acids (LCHFA) accumulate in long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. Affected patients usually present severe neonatal symptoms involving cardiac and hepatic functions, although long-term neurological abnormalities are also commonly observed. Since the underlying mechanisms of brain damage are practically unknown and have not been properly investigated, we studied the effects of LCHFA on important parameters of mitochondrial homeostasis in isolated mitochondria from cerebral cortex of developing rats. 3-Hydroxytetradecanoic acid (3 HTA) reduced mitochondrial membrane potential, NAD(P)H levels, Ca(2+) retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca(2+)-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca(2+) uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca(2+), respectively. 3-Hydroxydodecanoic and 3-hydroxypalmitic acids, that also accumulate in LCHAD and MTP deficiencies, similarly induced mitochondrial swelling and decreased ATP content, but to a variable degree pending on the size of their carbon chain. It is proposed that mPTP opening induced by LCHFA disrupts brain bioenergetics and may contribute at least partly to explain the neurologic dysfunction observed in patients affected by LCHAD and MTP deficiencies.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Cardiomiopatías/metabolismo , Corteza Cerebral/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Ácidos Láuricos/farmacología , Errores Innatos del Metabolismo Lipídico/metabolismo , Mitocondrias/efectos de los fármacos , Miopatías Mitocondriales/metabolismo , Proteína Trifuncional Mitocondrial/metabolismo , Ácidos Mirísticos/farmacología , Enfermedades del Sistema Nervioso/metabolismo , Ácidos Palmíticos/farmacología , Rabdomiólisis/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Cardiomiopatías/patología , Corteza Cerebral/metabolismo , Citocromos c/metabolismo , Homeostasis , Peróxido de Hidrógeno/metabolismo , Errores Innatos del Metabolismo Lipídico/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Miopatías Mitocondriales/patología , Poro de Transición de la Permeabilidad Mitocondrial , Dilatación Mitocondrial/efectos de los fármacos , NADP/metabolismo , Enfermedades del Sistema Nervioso/patología , Oxidantes/metabolismo , Ratas , Ratas Wistar , Rabdomiólisis/patologíaRESUMEN
PURPOSE OF REVIEW: Coenzyme Q (CoQ) is a vital component of the mitochondrial respiratory chain. A number of patients with CoQ deficiency presented with different clinical phenotypes, often affecting skeletal muscle, and responded well to CoQ supplementation. We discuss recent advances in this field with special attention to muscle involvement. RECENT FINDINGS: The identification of genetic defects causing CoQ deficiency has allowed to distinguish primary forms, due to mutations in biosynthetic genes, from secondary defects caused either by mutations in genes unrelated to CoQ biosynthesis or by nongenetic factors. To date, none of the patients with genetically proven primary deficiency presented with an exclusively (or prominently) myopathic phenotype. Most patients with myopathy were found to harbor other genetic defects (mutations in electron-transferring-flavoprotein dehydrogenase or mitochondrial DNA). The majority of patients with CoQ deficiency still lack a genetic diagnosis. The pathogenesis of CoQ deficiency cannot be attributed solely to the bioenergetic defect, suggesting that other roles of CoQ, including its antioxidant properties or its role in pyrimidine metabolism, may also play crucial roles. SUMMARY: Early recognition of CoQ deficiency is essential to institute appropriate and timely treatment, thus avoiding irreversible tissue damage.
Asunto(s)
Enfermedades Metabólicas/enzimología , Músculo Esquelético/enzimología , Enfermedades Musculares/enzimología , Ubiquinona/deficiencia , Humanos , Enfermedades Metabólicas/patología , Miopatías Mitocondriales/enzimología , Miopatías Mitocondriales/patología , Músculo Esquelético/patología , Enfermedades Musculares/patología , Ubiquinona/genéticaRESUMEN
The importance of mitochondrial biogenesis in the pathogenesis of mitochondrial diseases has been widely recognised but little is known about it with regard to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) syndrome. Since such knowledge would contribute to the understanding of the pathogenesis of this disease, we designed a study to provide comprehensive overview of mitochondrial biogenesis in cybrid cells harboring NARP mutation (8993T>G). We also used Rho0 cells with the same nuclear background to show that distinct mtDNA defects lead to distinct cellular responses irrespective of nuclear genome. Mitochondrial biogenesis is regulated by mitochondria-to-nucleus (retrograde) communication which depends on intracellular signaling pathways sensitive to ROS. Since we previously found that selenite lowered ROS in NARP cybrids, we hypothesised that selenite could also modulate mitochondrial biogenesis in these cells. Although the mitochondrial mass was not changed in NARP cybrids, we showed the compensatory upregulation of respiratory chain subunits which prompted us to investigate the transcription factors that regulate their expression such as PGC-1α, NRFs, and TFAM. Selenite supplementation increased the level of NRF1 and nuclear accumulation of NRF2, but we did not detect any major changes in the levels of investigated respiratory chain proteins. These subtle changes in mitochondrial biogenesis in response to selenite treatment support the hypothesis that selenite could be considered as a potential therapeutic agent of NARP syndrome due to its antioxidant properties. Moreover, it could also be tested with regard to other mitochondrial disorders associated with ROS overproduction.
Asunto(s)
ADN Mitocondrial/genética , Mitocondrias/genética , Miopatías Mitocondriales/tratamiento farmacológico , Miopatías Mitocondriales/genética , Mutación , Retinitis Pigmentosa/tratamiento farmacológico , Retinitis Pigmentosa/genética , Selenito de Sodio/administración & dosificación , Línea Celular Tumoral , Células Cultivadas , Citocromos c/metabolismo , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Suplementos Dietéticos , Fibroblastos/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Inmunohistoquímica , Canales Iónicos/metabolismo , Mitocondrias/metabolismo , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/patología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fosforilación , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Factores de Transcripción/metabolismo , Proteína Desacopladora 3RESUMEN
PURPOSE OF REVIEW: Treatment options for mitochondrial myopathies remain limited despite rapid advances in the understanding of the molecular basis of these conditions. Existing therapies continue to be evaluated and novel treatment strategies are starting to appear on the horizon. RECENT FINDINGS: Exercise training continues to show promise as a method of improving exercise tolerance and enhancing oxidative capacity. Coenzyme Q10 deficiency appears to be a relatively common finding in mitochondrial disorders and is likely to benefit from exogenous supplementation. Large-scale randomized clinical trials to evaluate these treatment options are now underway and this represents one of the most important developments in recent years. Activation of the peroxisome proliferator-activated receptor/peroxisome proliferator-activated receptor-gamma coactivator-1alpha pathway has been shown to induce mitochondrial biogenesis leading to a delayed onset of myopathy and prolonged lifespan in mouse models. A ketogenic diet has also been found to induce mitochondrial biogenesis in mice with mitochondrial myopathy. SUMMARY: Therapeutic trials of exercise training and coenzyme Q10 supplementation should continue to be offered to patients with mitochondrial myopathies pending the results of evaluation in randomized clinical trials. Further investigation of peroxisome proliferator-activated receptor/peroxisome proliferator-activated receptor-gamma coactivator-1alpha pathway activation, ketogenic diets and other new strategies is required.
Asunto(s)
Miopatías Mitocondriales/terapia , Animales , Dieta Cetogénica , Suplementos Dietéticos , Terapia por Ejercicio , Humanos , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/patología , Miopatías Mitocondriales/fisiopatología , Mutación , PPAR gamma/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
Neuromuscular disorders with defects in the mitochondrial ATP-generating system affect a large number of children and adults worldwide, but remain without treatment. We used a mouse model of mitochondrial myopathy, caused by a cytochrome c oxidase deficiency, to evaluate the effect of induced mitochondrial biogenesis on the course of the disease. Mitochondrial biogenesis was induced either by transgenic expression of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) in skeletal muscle or by administration of bezafibrate, a PPAR panagonist. Both strategies successfully stimulated residual respiratory capacity in muscle tissue. Mitochondrial proliferation resulted in an enhanced OXPHOS capacity per muscle mass. As a consequence, ATP levels were conserved resulting in a delayed onset of the myopathy and a markedly prolonged life span. Thus, induction of mitochondrial biogenesis through pharmacological or metabolic modulation of the PPAR/PGC-1alpha pathway promises to be an effective therapeutic approach for mitochondrial disorders.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Mitocondrias Musculares/metabolismo , Miopatías Mitocondriales/tratamiento farmacológico , Miopatías Mitocondriales/genética , PPAR gamma/metabolismo , Transactivadores/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Bezafibrato/administración & dosificación , Deficiencia de Citocromo-c Oxidasa/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Femenino , Ratones , Ratones Endogámicos , Ratones Transgénicos , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/genética , Miopatías Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , PPAR gamma/agonistas , PPAR gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tasa de Supervivencia , Transactivadores/genética , Factores de Transcripción , TransgenesRESUMEN
Pyrophosphatases (PPases) catalyze the hydrolysis of inorganic pyrophosphate generated in several cellular enzymatic reactions. A novel human pyrophosphatase cDNA encoding a 334-amino-acid protein approximately 60% identical to the previously identified human cytosolic PPase was cloned and characterized. The novel enzyme, named PPase-2, was enzymatically active and catalyzed hydrolysis of pyrophosphate at a rate similar to that of the previously identified PPase-1. A functional mitochondrial import signal sequence was identified in the N-terminus of PPase-2, which targeted the enzyme to the mitochondrial matrix. The human pyrophosphatase 2 gene (PPase-2) was mapped to chromosome 4q25 and the 1.4-kb mRNA was ubiquitously expressed in human tissues, with highest levels in muscle, liver, and kidney. The yeast homologue of the mitochondrial PPase-2 is required for mitochondrial DNA maintenance and yeast cells lacking the enzyme exhibit mitochondrial DNA depletion. We sequenced the PPA2 gene in 13 patients with mitochondrial DNA depletion syndromes (MDS) of unknown cause to determine if mutations in the PPA2 gene of these patients were associated with this disease. No pathogenic mutations were identified in the PPA2 gene of these patients and we found no evidence that PPA2 gene mutations are a common cause of MDS in humans.
Asunto(s)
Proteínas Mitocondriales/genética , Pirofosfatasas/genética , Secuencia de Aminoácidos , Northern Blotting , Cloruro de Calcio/farmacología , Línea Celular Tumoral , Mapeo Cromosómico , Cromosomas Humanos Par 4/genética , Clonación Molecular , ADN Complementario/química , ADN Complementario/genética , Difosfatos/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HeLa , Humanos , Hidrólisis/efectos de los fármacos , Pirofosfatasa Inorgánica/genética , Pirofosfatasa Inorgánica/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Miopatías Mitocondriales/enzimología , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Señales de Clasificación de Proteína/genética , Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Síndrome , TransfecciónRESUMEN
Exercise therapy improves mitochondrial function in patients with mitochondrial myopathy (MM). We undertook this study to determine the metabolic abnormalities that are improved by exercise therapy. This study identified metabolic pathology using (31)P-magnetic resonance spectroscopy and magnetic resonance imaging (MRI) in a group of patients with MM compared to a control group matched for age, gender, and physical activity. We also observed the effect of exercise therapy for 12 weeks on muscle metabolism and physical function in the MM group. During muscle activity, there was impaired responsiveness of the mitochondria to changes in cytosolic adenosine diphosphate concentration, increased dependence on anaerobic energy pathways, and an adaptive increase in proton efflux in patients with MM. Following exercise therapy, mitochondrial function and muscle mass improved without any change in proton efflux rate. These metabolic findings were accompanied by improvements in functional ability. We conclude that there are significant metabolic differences between patients with MM and a control population, independent of age, gender, and physical activity. Exercise therapy can assist in improving mitochondrial function in MM patients.
Asunto(s)
Ejercicio Físico/fisiología , Miopatías Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Adulto , Algoritmos , Prueba de Esfuerzo , Terapia por Ejercicio , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Miopatías Mitocondriales/patología , Músculo Esquelético/patología , Tamaño de los Órganos , Fósforo/metabolismo , ProtonesRESUMEN
We have described that administration of seeds or parts of the seed of Senna occidentalis (coffee senna) for long periods, induces histochemical changes in the skeletal muscles of hens and rats that are characteristic of a mitochondrial myopathy--as decrease of SDH and COX activity, with some COX negative fibers. In this experimental model of mitochondrial myopathy, as in many human mitochondrial diseases, there is a random distribution of COX negative fibers. Some fibers are completely COX negative while others are partially negative and others are completely positive. In the present work we have studied the distribution of COX negative mitochondria at transmission electron microscopy in skeletal muscle of rats in this experimental myopathy. In myofibers of intoxicated animals the expression of COX was heterogeneous. The histochemical reaction was observed in the internal membrane (more evident in mitochondrial cristae) of all mitochondria of some myofibers, while it was almost absent in other myofibers. In these myofibers the great part of the mitochondria were negative for COX reaction while other ones had a weak expression of this enzyme (dot or focal expression of COX). Our results indicated that the COX mitochondrial activity is heterogeneously impaired in myofibers of rats intoxicated with S. occidentalis. These abnormalities remember those observed in some types of human mitochondrial myopathies.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa , Mitocondrias/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Semillas/toxicidad , Senna , Dieta , Modelos Animales de Enfermedad , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Miopatías Mitocondriales/enzimología , Miopatías Mitocondriales/etiología , Miopatías Mitocondriales/patología , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/ultraestructura , Músculo Esquelético/enzimología , Músculo Esquelético/ultraestructura , Plantas Medicinales , Extracto de Senna/toxicidad , Senna/químicaRESUMEN
We describe a patient with progressive myoclonus epilepsy (PME), white matter hyperintensities in the corpus callosum, cerebral hemispheres, and left cerebral peduncle on magnetic resonance imaging (MRI), and positive oligoclonal bands. A phosphorus magnetic resonance spectrum was compatible with mitochondrial dysfunction. Abnormal white matter signals are not a feature of the known PME syndromes, although they occur in Leber's hereditary optic neuropathy (LHON). These abnormalities oriented the diagnosis toward mitochondrial disease.
Asunto(s)
Imagen por Resonancia Magnética/estadística & datos numéricos , Espectroscopía de Resonancia Magnética/estadística & datos numéricos , Miopatías Mitocondriales/diagnóstico , Epilepsias Mioclónicas Progresivas/diagnóstico , Adulto , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Humanos , Masculino , Miopatías Mitocondriales/patología , Miopatías Mitocondriales/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Epilepsias Mioclónicas Progresivas/fisiopatología , FósforoRESUMEN
Different tissues display distinct sensitivities to defective mitochondrial oxidative phosphorylation (OXPHOS). Tissues highly dependent on oxygen such as the cardiac muscle, skeletal and smooth muscle, the central and peripheral nervous system, the kidney, and the insulin-producing pancreatic beta-cell are especially susceptible to defective OXPHOS. There is evidence that defective OXPHOS plays an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. Defective OXPHOS may be caused by abnormal mitochondrial biosynthesis due to inherited or acquired mutations in the nuclear (n) or mitochondrial (mt) deoxyribonucleic acid (DNA). For instance, the presence of a mutation of the mtDNA in the pancreatic beta-cell impairs adenosine triphosphate (ATP) generation and insulin synthesis. The nuclear genome controls mitochondrial biosynthesis, but mtDNA has a much higher mutation rate than nDNA because it lacks histones and is exposed to the radical oxygen species (ROS) generated by the electron transport chain, and the mtDNA repair system is limited. Defective OXPHOS may be caused by insufficient fuel supply, by defective electron transport chain enzymes (Complexes I - IV), lack of the electron carrier coenzyme Q10, lack of oxygen due to ischemia or anemia, or excessive membrane leakage, resulting in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase. Human tissues can counteract OXPHOS defects by stimulating mitochondrial biosynthesis; however, above a certain threshold the lack of ATP causes cell death. Many agents affect OXPHOS. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS and induce the 'topical' phase of gastrointestinal ulcer formation. Uncoupled mitochondria reduce cell viability. The Helicobacter pylori induces uncoupling. The uncoupling that opens the membrane pores can activate apoptosis. Cholic acid in experimental atherogenic diets inhibits Complex IV, cocaine inhibits Complex I, the poliovirus inhibits Complex II, ceramide inhibits Complex III, azide, cyanide, chloroform, and methamphetamine inhibit Complex IV. Ethanol abuse and antiviral nucleoside analogue therapy inhibit mtDNA replication. By contrast, melatonin stimulates Complexes I and IV and Gingko biloba stimulates Complexes I and III. Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.
Asunto(s)
Mitocondrias/metabolismo , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/patología , Fosforilación Oxidativa , Adenosina Trifosfato/metabolismo , Animales , ADN Mitocondrial/genética , Humanos , Encefalomiopatías Mitocondriales/genética , Miopatías Mitocondriales/genéticaRESUMEN
We report a man who developed selenium-deficient myopathy during long-term parenteral nutrition. Muscle biopsy showed marked mitochondrial depletion in the deep sarcoplasm and enlarged mitochondria at the periphery mainly in type 2 fibers. Muscle weakness improved gradually after the second course of selenium supplementation. The peculiar mitochondrial abnormalities in muscle fibers appear to play a key role in the pathogenesis of selenium-deficient myopathy.
Asunto(s)
Mitocondrias/patología , Miopatías Mitocondriales/etiología , Miopatías Mitocondriales/patología , Enfermedades Musculares/etiología , Enfermedades Musculares/patología , Selenio/deficiencia , Adulto , Humanos , Masculino , Microscopía Electrónica , Miopatías Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/fisiopatología , Músculos/patología , Enfermedades Musculares/tratamiento farmacológico , Nutrición Parenteral/efectos adversos , Selenio/uso terapéutico , Factores de TiempoRESUMEN
Plants of the genus Senna (formerly Cassia) have been recognized as the cause of a natural and experimental syndrome of muscle degeneration frequently leading to death in animals. Histologically, it demonstrated skeletal and cardiac muscle necrosis, with floccular degeneration and proliferation of sarcolemmal nuclei. Recently, it was described as an experimental model of mitochondrial myopathy in hens chronically treated with Senna occidentalis. Currently, skeletal muscles of chicks intoxicated with seeds of the poisonous plant S. occidentalis were studied by histochemistry and electron microscopy. Since birth, the birds were fed ground dried seeds of this plant with a regular chicken ration at a dose of 4% for 11 days. Microscopic examination revealed, besides muscle-fiber atrophy, lipid storage in most fibers and a moderate amount of cytochrome oxidase-negative fibers. By electron microscopy, enlarged mitochondria with disrupted or excessively branched cristae were seen. This picture was characteristic of mitochondrial myopathy. These findings have hitherto remained unnoticed in skeletal muscle of young birds treated with S. occidentalis.
Asunto(s)
Alimentación Animal/toxicidad , Pollos , Miopatías Mitocondriales/veterinaria , Músculo Esquelético/efectos de los fármacos , Enfermedades de las Aves de Corral/inducido químicamente , Extracto de Senna/toxicidad , Animales , Atrofia/inducido químicamente , Atrofia/patología , Atrofia/veterinaria , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/ultraestructura , Miopatías Mitocondriales/inducido químicamente , Miopatías Mitocondriales/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Oxidorreductasas/metabolismo , Plantas Tóxicas , Enfermedades de las Aves de Corral/patología , SemillasRESUMEN
Histochemical and electron microscopic studies of biceps femoris, pectoralis major and rectus femoris of chronically treated birds with seeds of the poisonous plant Senna occidentalis (0.2% external/internal tegment), were performed. The muscles had similar features of human mitochondrial myopathy as ragged-red fibers, cytochrome-oxidase negative fibers, and weak activity of the oxidative enzymes. Fibers with lipid storage were also present. Acid phosphatase activity in rare muscle fibers was also detected, and represents probably a secondary degenerative process. By electron microscopy, enlarged mitochondria with disrupted or excessively branched cristae were seen. The present study presents a new experimental model of mitochondrial myopathy that may be useful for the best knowledge of this group of diseases and for experimental trials of drugs that could reverse the mitochondrial impairment in the mitochondrial myopathies.
Asunto(s)
Miopatías Mitocondriales/etiología , Intoxicación por Plantas/patología , Semillas , Extracto de Senna , Animales , Pollos , Enfermedad Crónica , Histocitoquímica , Humanos , Miopatías Mitocondriales/patología , Valores de ReferenciaRESUMEN
A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbances resolved within three weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a still unreported feature of podophyllin toxicity.
Asunto(s)
Miopatías Mitocondriales/inducido químicamente , Podofilino/envenenamiento , Adulto , Humanos , Masculino , Miopatías Mitocondriales/patología , Necrosis , Sepsis , SuicidioRESUMEN
A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbance resolved within theree weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a sitill unreported feature of podophillin toxicity.