RESUMO
Defects of mitoribosome assembly with destabilization of mitochondrial ribosomal proteins and subsequent aberrant mitochondrial translation machinery are one of the emerging categories of human mitochondrial disease. Mitochondrial translation deficiency constitutes a growing cause of combined oxidative phosphorylation deficiency and overall causes a set of clinically heterogeneous multi-systemic diseases. We present here the sixth individual with combined oxidative phosphorylation deficiency-9 (COXPD9) secondary to a likely pathogenic homozygous MRPL3 variant c.571A > C; p.(Thr191Pro). MRPL3 encodes a large mitochondrial ribosome subunit protein, impairing the mitochondrial translation and resulting in multisystem disease. Similar to previously reported individuals, this reported female proband presented with psychomotor retardation, sensorineural hearing loss, hypertrophic cardiomyopathy, failure to thrive, and lactic acidosis. Further, she has additional, previously unreported, features including Leigh syndrome, cataracts, hypotonia, scoliosis, myopathy, exercise intolerance, childhood-onset cardiomyopathy, and microcephaly. This subject is the oldest reported individual with COXPD9. This report also summarizes the clinical and molecular data of the previously reported individuals with COXPD9 to describe the full phenotypic spectrum.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Proteínas Ribossômicas/genética , Alelos , Substituição de Aminoácidos , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Porto Rico , IrmãosRESUMO
L-Arginine (L-ARG) supplementation has been suggested as a therapeutic option in several diseases, including Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like syndrome (MELAS), arguably the most common mitochondrial disease. It is suggested that L-ARG, a nitric oxide (NO) precursor, can restore NO levels in blood vessels, improving cerebral blood flow. However, NO also participates in mitochondrial processes, such as mitochondrial biogenesis, the regulation of the respiratory chain, and oxidative stress. This study investigated the effects of L-ARG on mitochondrial function, nitric oxide synthesis, and nitro-oxidative stress in cell lines harboring the MELAS mitochondrial DNA (mtDNA) mutation (m.3243A>G). We evaluated mitochondrial enzyme activity, mitochondrial mass, NO concentration, and nitro-oxidative stress. Our results showed that m.3243A>G cells had increased NO levels and protein nitration at basal conditions. Treatment with L-ARG did not affect the mitochondrial function and mass but reduced the intracellular NO concentration and nitrated proteins in m.3243A>G cells. The same treatment led to opposite effects in control cells. In conclusion, we showed that the main effect of L-ARG was on protein nitration. Lowering protein nitration is probably involved in the mechanism related to L-ARG supplementation benefits in MELAS patients.
Assuntos
Arginina/farmacologia , DNA Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Humanos , Doenças Mitocondriais/genética , Mutação , Óxido Nítrico/biossínteseRESUMO
Mitochondria play an important role in cell life and in the regulation of cell death. In addition, mitochondrial dysfunction contributes to a wide range of neuropathologies. The nucleoside Guanosine (GUO) is an endogenous molecule, presenting antioxidant properties, possibly due to its direct scavenging ability and/or from its capacity to activate the antioxidant defense system. GUO demonstrate a neuroprotective effect due to the modulation of the glutamatergic system and maintenance of the redox system. Thus, considering the few studies focused on the direct effects of GUO on mitochondrial bioenergetics, we designed a study to evaluate the in vitro effects of GUO on rat mitochondrial function, as well as against Ca2+-induced impairment. Our results indicate that GUO prevented mitochondrial dysfunction induced by Ca2+ misbalance, once GUO was able to reduce mitochondrial swelling in the presence of Ca2+, as well as ROS production and hydrogen peroxide levels, and to increase manganese superoxide dismutase activity, oxidative phosphorylation and tricarboxylic acid cycle activities. Our study indicates for the first time that GUO could direct prevent the mitochondrial damage induced by Ca2+ and that these effects were not related to its scavenging properties. Our data indicates that GUO could be included as a new pharmacological strategy for diseases linked to mitochondrial dysfunction.
Assuntos
Cálcio/metabolismo , Guanosina/farmacologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Masculino , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de la coenzima Q10, carnitina y riboflavina respecto a su uso en pacientes con enfermedades mitocondriales. Aspectos Generales: Las mitocondrias son organelas complejas de doble membrana que cuentan con un ADN propio, heredado de la madre. Subojetivo es producir energia a partir de los nutrientes en fora de calor y ATP, mediante la respiración. El proceso por el cual se produce la energía es conocido como fosforilación oxidativa y se lleva a cabo en la cadena respiratoria de las mitocondrias, también llamada cadena transportadora de electrones. Tecnologia Sanitária de Interés: Coenzima Q10: La coenzima Q10, también conocida como ubiquinona, es una quinona soluble en grasas , sintetizada en la mitocondria y que se encuentra presente en la membranas celulares. La coenzima Q'0 endógena es producida por el organismo como parte de la vía de producción del colestereol, mientras que la exógena es ingerida por la dieta como ubiquinona (forma oxidada) y ubuquinol (forma reducida). Esta molécula se encuentra presente en todas las células del organismo, en mayor concentración en el tejido del cerebro, corazón, riñones, e hígado. Carnitina: La carnitina, presente en el organismo y en los alimentos como I-carnitina, es un aminoácido sintetizado en el tejido muscular, renal y hepático a partir de los aminoácidos l-lisina yl-metionina. Existen fuentes exógenas de l-carnitina como las carnes rojas, el pescado, el pollo e la leche. Esta molécula cumple una función importante en el metabolismo de ácidos grasos, ya que promueve la utilización de la grasa almacenada en el organismo como fuente de energia. Especificamente, la L-carnitina es un transportador de lípidos que permite el ingreso de las cadenas de ácidos grasos a la matriz mitocondrial para ser convertidos en energía a través del proceso de la beta-oxidación. Riboflavina: La riboflavina (vitamina B2) es una vitamina hidrosolubre que se encuentra la manera natural en los alimentos de origen animal y vegetal, y puede ser producida también por la microbiota intestinal. Esta vitamina se absorve en el intestino delgado proximal y, cuando es consumida en exceso, es excretada por la orina y/o almacenada en concetraciones reducidas en el hígado, riñones, y corazón. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de literatura científica en relación a la eficacia y seguridad del uso de la coenzima Q10, carnitina y riboflavina en pacientes con enfermedades mitocondriales (EM). Sedio preferencia a guías de práctica clínica, revisiones sistemáticas con o sin meta-análisis y ensayos clínicos aleatrorizados. RESULTADOS: Sinopsis de la Evidencia: Se realizó la busqueda bibliográfica y de evidencia científica que sustente el uso de coenzima Q10, carnitina y riboflavina en pacientes con diganóstico de enfermedades mitocondriales (EM). CONCLUSIONES: En la presente evaluación de tecnología sanitária se presenta a la evidencia recabada sobre el beneficio de la coenzima Q10, carnitina y riboflavina en pacientes con enfermedades mitocondriales. La evidencia encontrada que evalúa el uso de estos compuestos en pacientes con enfermedades mitocondriales es escasa. Se ha identificado evidencia proveniente de tres ensayos clínicos y un estudio obervacional. Ninguno de los estudios evaluó los tres suplementos en conjunto como una sola intervención. El Instituto de evaluación en Salud e Investigación-IETSI, aprueba el uso de la coenzima Q10, carnitina y riboflavina en pacientes con enfermedades mitocondriales. El presente Dictamen Preliminar tiene una vigencia de dos años a partir de la fecha de publicación.
Assuntos
Humanos , Doenças Mitocondriais/tratamento farmacológico , Carnitina/administração & dosagem , Combinação de Medicamentos , Riboflavina/administração & dosagem , Avaliação da Tecnologia Biomédica , Resultado do Tratamento , Ubiquinona/administração & dosagemRESUMO
Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca2+ homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Lesões Encefálicas Traumáticas , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Doenças Mitocondriais , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Guanosina/administração & dosagem , Masculino , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Oxirredução/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Migraine is the most frequent type of headache in children. In the 1980s, scientists first hypothesized a connection between migraine and mitochondrial (mt) disorders. More recent studies have suggested that at least some subtypes of migraine may be related to a mt defect. Different types of evidence support a relationship between mitochondria (mt) and migraine: (1) Biochemical evidence: Abnormal mt function translates into high intracellular penetration of Ca(2+), excessive production of free radicals, and deficient oxidative phosphorylation, which ultimately causes energy failure in neurons and astrocytes, thus triggering migraine mechanisms, including spreading depression. The mt markers of these events are low activity of superoxide dismutase, activation of cytochrome-c oxidase and nitric oxide, high levels of lactate and pyruvate, and low ratios of phosphocreatine-inorganic phosphate and N-acetylaspartate-choline. (2) Morphologic evidence: mt abnormalities have been shown in migraine sufferers, the most characteristic ones being direct observation in muscle biopsy of ragged red and cytochrome-c oxidase-negative fibers, accumulation of subsarcolemmal mt, and demonstration of giant mt with paracrystalline inclusions. (3) Genetic evidence: Recent studies have identified specific mutations responsible for migraine susceptibility. However, the investigation of the mtDNA mutations found in classic mt disorders (mt encephalomyopathy with lactic acidosis and stroke-like episodes, myoclonus epilepsy with ragged red fibers, Kearns-Sayre syndrome, and Leber hereditary optic neuropathy) has not demonstrated any association. Recently, 2 common mtDNA polymorphisms (16519CâT and 3010GâA) have been associated with pediatric cyclic vomiting syndrome and migraine. Also, POLG mutations (eg, p.T851 A, p.N468D, p.Y831C, p.G517V, and p.P163S) can cause disease through impaired replication of mtDNA, including migraine. Further studies to investigate the relationship between mtDNA and migraine will require very large sample sizes to obtain statistically significant results. (4) Therapeutic evidence: Several agents that have a positive effect on mt metabolism have shown to be effective in the treatment of migraines. The agents include riboflavin (B2), coenzyme Q10, magnesium, niacin, carnitine, topiramate, and lipoic acid. Further study is warranted to learn how mt interact with other factors to cause migraines. This will facilitate the development of new and more specific treatments that will reduce the frequency or severity or both of this disease.
Assuntos
Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , DNA Mitocondrial/genética , Humanos , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/tratamento farmacológico , Doenças Mitocondriais/complicações , Doenças Mitocondriais/tratamento farmacológico , Mutação , Vitaminas/uso terapêuticoAssuntos
DNA Mitocondrial/genética , Micronutrientes/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Mutação , Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Ubiquinona/análogos & derivados , Criança , Humanos , Masculino , Doenças Mitocondriais/genética , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Reação em Cadeia da Polimerase , Irmãos , Resultado do Tratamento , Ubiquinona/uso terapêutico , Acuidade Visual/efeitos dos fármacos , Campos Visuais/efeitos dos fármacosRESUMO
Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.
Assuntos
Ataxia Cerebelar/tratamento farmacológico , Corticosteroides/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia Cerebelar/etiologia , Doença Crônica , Ataxia de Friedreich/tratamento farmacológico , Humanos , Proteínas de Ligação ao Ferro/fisiologia , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Ubiquinona/deficiência , Vitamina E/uso terapêutico , Deficiência de Vitamina E/complicações , FrataxinaRESUMO
Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederichs ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.
Assuntos
Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/etiologia , Ataxia de Friedreich/tratamento farmacológico , Ataxia/tratamento farmacológico , Corticosteroides/uso terapêutico , Debilidade Muscular/tratamento farmacológico , Deficiência de Vitamina E/complicações , Doença Crônica , Doenças Mitocondriais/tratamento farmacológico , Humanos , Proteínas de Ligação ao Ferro/fisiologia , Ubiquinona/deficiência , Vitamina E/uso terapêuticoRESUMO
Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederichs ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.