Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders.
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.
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México.
Estefanía
E
Ochoa-Ruiz
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México.
Rodrigo
R
Díaz-Ruiz
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México.
Alaín de J
Ade J
Hernández-Vázquez
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México.
Isabel
I
Ibarra-González
Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México D.F., México.
Alma
A
Ortiz-Plata
Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México D.F., México.
Daniel
D
Rembao
Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, México D.F., México.
Daniel
D
Ortega-Cuéllar
INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR, 8104 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Benoit
B
Viollet
Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F., México.
Salvador
S
Uribe-Carvajal
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México.
José Ahmed
JA
Corella
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México y del Instituto Nacional de Pediatría, México D.F., México. Electronic address: velare@unam.mx.
Antonio
A
Velázquez-Arellano
D000818:Animals; D001710:Biotin / Q000172:deficiency* / Q000378:metabolism*; D019731:Carbon-Nitrogen Ligases / Q000378:metabolism; D002331:Carnitine / Q000008:administration & dosage / Q000378:metabolism; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D063306:Mitophagy; D010085:Oxidative Phosphorylation; D011766:Pyruvate Carboxylase / Q000378:metabolism; D051381:Rats
D015850:Interleukin-6; D001710:Biotin; D003576:Electron Transport Complex IV; D019731:Carbon-Nitrogen Ligases; C019791:biotin carboxylase; D011766:Pyruvate Carboxylase; D002331:Carnitine
Disrupted anaplerosis; Impaired oxidative phosphorylation; Inborn errors of metabolism; Mitochondrial damage and biotin deprivation