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

Molecular Genetics and Metabolism
Estefanía Ochoa-RuizAntonio Velázquez-Arellano

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 concom...Continue Reading

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Citations

Mar 22, 2020·British Journal of Pharmacology·Daniela BuonvicinoAlberto Chiarugi
Jul 14, 2020·Journal of Medicinal Chemistry·Salvatore BongarzoneAntony Gee
May 7, 2021·Investigative Ophthalmology & Visual Science·Ying WangChen-Wei Pan

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