Molecular Genetics and Metabolism 2015-11-01

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

Estefanía Ochoa-Ruiz, Rodrigo Díaz-Ruiz, Alaín de J Hernández-Vázquez, Isabel Ibarra-González, Alma Ortiz-Plata, Daniel Rembao, Daniel Ortega-Cuéllar, Benoit Viollet, Salvador Uribe-Carvajal, José Ahmed Corella, Antonio Velázquez-Arellano

Index: Mol. Genet. Metab. 116 , 204-14, (2015)

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Abstract

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.