ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency.

Autor: Vázquez-Fonseca L; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, and IRP Città della Speranza, 35100 Padova, Italy., Schaefer J; Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany., Navas-Enamorado I; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; Boston University School of Medicine, Boston, MA 02118, USA.; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA., Santos-Ocaña C; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Hernández-Camacho JD; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Guerra I; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain., Cascajo MV; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Sánchez-Cuesta A; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Horvath Z; Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany., Siendones E; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain., Jou C; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain.; Clinical Chemistry and Pathology Departments, Institut de Recerca Sant Joan de Déu, 08000 Barcelona, Spain., Casado M; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain.; Clinical Chemistry and Pathology Departments, Institut de Recerca Sant Joan de Déu, 08000 Barcelona, Spain., Gutiérrez P; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain., Brea-Calvo G; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., López-Lluch G; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Fernández-Ayala DJM; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Cortés-Rodríguez AB; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Rodríguez-Aguilera JC; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain., Matté C; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul. CEP 90035-003, Porto Alegre, RS, Brazil., Ribes A; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain.; Secciód'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica I Genètica Molecular, Hospital Clinic, 08000 Barcelona, Spain., Prieto-Soler SY; División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain., Dominguez-Del-Toro E; División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain., Francesco AD; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA., Aon MA; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA., Bernier M; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA., Salviati L; Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, and IRP Città della Speranza, 35100 Padova, Italy., Artuch R; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain.; Clinical Chemistry and Pathology Departments, Institut de Recerca Sant Joan de Déu, 08000 Barcelona, Spain., Cabo R; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA., Jackson S; Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany., Navas P; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain. pnavas@upo.es.; CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain. pnavas@upo.es.
Jazyk: angličtina
Zdroj: Journal of clinical medicine [J Clin Med] 2019 Sep 02; Vol. 8 (9). Date of Electronic Publication: 2019 Sep 02.
DOI: 10.3390/jcm8091374
Abstrakt: Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2 , a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data showed that A dck 2 +/- mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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