Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders

Ochoa Ruiz, Estefanía

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Título :	Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders
Creador:	Ochoa Ruiz, Estefanía
Nivel de acceso:	Open access
Palabras clave :	Animales Biotina - deficiencia Biotina - metabolismo Ligasas de Carbono-Nitrógeno - metabolismo Carnitina - administración & dosificación Carnitina - metabolismo Células Cultivadas Ciclo del Ácido Cítrico Complejo IV de Transporte de Electrones - metabolismo Metabolismo Energético Interleucina-6 - metabolismo Errores Innatos del Metabolismo - genética Errores Innatos del Metabolismo - metabolismo Errores Innatos del Metabolismo - patología Ratones Noqueados Mitocondrias - metabolismo Mitocondrias - ultraestructura Degradación Mitocondrial Fosforilación Oxidativa Piruvato Carboxilasa - metabolismo Ratas Animals Biotin - deficiency Biotin - metabolism Carbon-Nitrogen Ligases - metabolism Carnitine - administration & dosage Carnitine - metabolism Cells, Cultured Citric Acid Cycle Electron Transport Complex IV - metabolism Energy Metabolism Interleukin-6 - metabolism Metabolism, Inborn Errors - genetics Metabolism, Inborn Errors - metabolism Metabolism, Inborn Errors - pathology Mice, Knockout Mitochondria - metabolism Mitochondria - ultrastructure Mitochondrial Degradation Oxidative Phosphorylation Pyruvate Carboxylase - metabolism Rats Errores innatos del metabolismo Anaplerosis interrumpido Fosforilación oxidativa deteriorada Daño mitocondrial y privación de biotina Inborn errors of metabolism Disrupted anaplerosis Impaired oxidative phosphorylation Mitochondrial damage and biotin deprivation
Descripción :	Certain inborn errors of metabolism result from deficiencies in biotin containing enzymes. These disorders are mimicked by dietary absence or insufficiency of biotin, ATP deficit being a major effect,whose responsible mechanisms have not been thoroughly studied. Here we show that in rats and cultured cells it is the result of reduced TCA cycle flow, partly due to deficient anaplerotic biotin-dependent pyruvate carboxylase. This is accompanied by diminished flow through the electron transport chain, augmented by deficient cytochrome c oxidase (complex IV) activity with decreased cytochromes and reduced oxidative phosphorylation. There was also severe mitochondrial damage accompanied by decrease of mitochondria, associated with toxic levels of propionyl CoA as shown by carnitine supplementation studies, which explains the apparently paradoxical mitochondrial diminution in the face of the energy sensor AMPK activation, known to induce mitochondria biogenesis. This idea was supported by experiments on AMPK knockout mouse embryonic fibroblasts (MEFs). The multifactorial ATP deficit also provides a plausible basis for the cardiomyopathy in patients with propionic acidemia, and other diseases.Additionally, systemic inflammation concomitant to the toxic state might explain our findings of enhanced IL-6, STAT3 and HIF-1α, associated with an increase of mitophagic BNIP3 and PINK proteins, which may further increase mitophagy. Together our results imply core mechanisms of energy deficit in several inherited metabolic disorders.
Colaborador(es) u otros Autores:	Díaz-Ruiz Rodrigo Hernández-Vázquez Alaín De J Ibarra-González Isabel Ortiz-Plata Alma Rembao Daniel Ortega-Cuellar Daniel Viollet Benoit Uribe-Carvajal Salvador Ahmed Corella José Velázquez-Arellano Antonio
Fecha de publicación :	2015
Tipo de publicación:	Artículo
Formato:	pdf
Identificador del Recurso :	10.1016/j.ymgme.2015.08.009
Fuente:	Molecular Genetics and Metabolism 116(3):204-214
URI :	http://repositorio.pediatria.gob.mx:8180/handle/20.500.12103/2119
Idioma:	eng
Aparece en las colecciones:	Artículos

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