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1.
Ann Neurol ; 76(4): 620-4, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25090982

RESUMEN

Energy metabolism could influence amyotrophic lateral sclerosis (ALS) and progressive lateral sclerosis (PLS) pathogenesis and the response to therapy. We developed a novel assay to simultaneously assess mitochondrial content and membrane potential in patients' skin fibroblasts. In ALS and PLS fibroblasts, membrane potential was increased and mitochondrial content decreased, relative to healthy controls. In ALS higher mitochondrial membrane potential correlated with age at diagnosis, and in PLS it correlated with disease severity. These unprecedented findings in ALS and PLS fibroblasts could shed new light onto disease pathogenesis and help in developing biomarkers to predict disease evolution and the individual response to therapy in motor neuron diseases.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Metabolismo Energético/fisiología , Fibroblastos/patología , Enfermedad de la Neurona Motora/patología , Piel/patología , Adulto , Anciano , Aldehídos , Biomarcadores , Humanos , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Persona de Mediana Edad , Rodaminas/metabolismo
2.
Addict Biol ; 18(2): 370-8, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22353491

RESUMEN

Sex differences exist in tobacco smoking behaviors. Nicotine, the primary addictive ingredient in tobacco smoke, indirectly affects γ-amino butyric acid (GABA) function. Previous studies reported sex-by-smoking interactions in brain GABA levels. The goal of the present study was to evaluate if there is a sex-by-smoking interaction at the GABA(A)-benzodiazepine receptors (GABA(A)-BZRs), as well as relationships between GABA(A)-BZR availability and behavioral variables before and after 1 week of smoking cessation. Twenty-six women (8 non-smokers, age 36.0 ± 13.4 years; 19 smokers, age 34.6 ± 8.9 years) and 25 men (8 non-smokers, age 37.9 ± 13.8 years; 17 smokers, 34.1 ± 12.4 years) were imaged using [123I]iomazenil and single-photon emission computed tomography. Smokers were imaged at baseline 7 hours after the last cigarette. A significantly great number of men were able to abstain from smoking for 1 week (P = 0.003). There were no significant differences in nicotine dependence and cigarette craving, mood or pain sensitivity between male and female smokers. There was a significant effect of gender across all brain regions (frontal, parietal, anterior cingulate, temporal and occipital cortices, and cerebellum; P < 0.05), with all women (smokers and non-smokers combined) having a higher GABA(A)-BZR availability than all men. There was a negative correlation between GABA(A)-BZR availability and craving (P ≤ 0.02) and pain sensitivity (P = 0.04) in female smokers but not male smokers. This study provides further evidence of a sex-specific regulation of GABA(A)-BZR availability in humans and demonstrates the potential for GABA(A)-BZRs to mediate tobacco smoking craving and pain symptoms differentially in female and male smokers.


Asunto(s)
Percepción del Dolor/fisiología , Receptores de GABA-A/metabolismo , Caracteres Sexuales , Síndrome de Abstinencia a Sustancias/metabolismo , Tabaquismo/metabolismo , Adulto , Síntomas Afectivos/psicología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Flumazenil/análogos & derivados , Moduladores del GABA , Humanos , Masculino , Persona de Mediana Edad , Nicotina/farmacología , Percepción del Dolor/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Cese del Hábito de Fumar , Síndrome de Abstinencia a Sustancias/diagnóstico por imagen , Síndrome de Abstinencia a Sustancias/fisiopatología , Tabaquismo/diagnóstico por imagen , Tabaquismo/fisiopatología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto Joven
3.
Cell Metab ; 27(5): 1007-1025.e5, 2018 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-29657030

RESUMEN

Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation. Furthermore, in a mouse model of mitochondrial myopathy, we show that increased oxidative αKG flux in muscle arises from enhanced alanine synthesis and release into blood, concomitant with accelerated amino acid catabolism from protein breakdown. Importantly, in this mouse model of mitochondriopathy, muscle amino acid imbalance is normalized by αKG supplementation. Taken together, our findings provide a rationale for αKG supplementation as a therapeutic strategy for mitochondrial myopathies.


Asunto(s)
ADN Mitocondrial/genética , Glutamina/metabolismo , Ácidos Cetoglutáricos , Mitocondrias , Miopatías Mitocondriales , Adaptación Fisiológica , Alanina/metabolismo , Animales , Modelos Animales de Enfermedad , Metabolismo Energético , Células HeLa , Humanos , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/uso terapéutico , Masculino , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/metabolismo , Mutación , Fosforilación Oxidativa
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