title: Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism.
abstract: Mutations on the mitochondrial-expressed Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene have been recently associated with a novel dietary-treatable form of autism. But, being a mitochondrial metabolism disease, little is known about the impact on mitochondrial performance. Here, we analyze the mitochondrial response to the BCKDK-deficiency in patient's primary fibroblasts by measuring bioenergetics, ultra-structural and dynamic parameters. A two-fold increase in superoxide anion production, together with a reduction in ATP-linked respiration and intracellular ATP levels (down to 60%) detected in mutants fibroblasts point to a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate. Ultrastructure analysis of BCKDK-deficient fibroblasts shows an increased number of elongated mitochondria, apparently associated with changes in the mediator of inner mitochondria membrane fusion, GTPase OPA1 forms, and in the outer mitochondrial membrane, mitofusin 2/MFN2. Our data support a possible hyperfusion response of BCKDK-deficient mitochondria to stress. Cellular fate also seems to be affected as these fibroblasts show an altered proportion of the cells on G0/G1 and G2/M phases. Knockdown of BCKDK gene in control fibroblasts recapitulates most of these features. Same BCKDK-knockdown in a MSUD patient fibroblasts unmasks the direct involvement of the accelerated BCAAs catabolism in the mitochondrial dysfunction. All these data give us a clue to understand the positive dietary response to an overload of branched-chain amino acids. We hypothesize that a combination of the current therapeutic option with a protocol that considers the oxidative damage and energy expenditure, addressing the patients' individuality, might be useful for the physicians.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), U-746 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, IDIPAZ, Universidad Autónoma de Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Oyarzabal
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), U-746 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, IDIPAZ, Universidad Autónoma de Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Bravo-Alonso
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, (CSIC-UAM), U-713 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Aragó
authors.affiliation: Servicio de Microscopía Electrónica, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Rejas
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), U-746 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, IDIPAZ, Universidad Autónoma de Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Merinero
authors.affiliation: Department of Neurology, Hospital Sant Joan de Déu (HSJD), U-703 CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García-Cazorla
authors.affiliation: Department of Biochemistry, Hospital Sant Joan de Déu (HSJD), U-703 CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Artuch
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), U-746 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, IDIPAZ, Universidad Autónoma de Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), U-746 Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, IDIPAZ, Universidad Autónoma de Madrid, Spain. Electronic address: mprodriguez@cbm.csic.es.
authors.forename: P
authors.initials: P
authors.lastname: Rodríguez-Pombo
mesh_terms: D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008375:Maple Syrup Urine Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D013481:Superoxides; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C415198:OPA1 protein, human
keywords: Autism; BCKDK-deficiency; Bioenergetics profile; Mitochondrial disease; Mitochondrial elongation; Unrestrained branched-chain amino acids catabolism