ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency
Por:
Vázquez-Fonseca L, Schaefer J, Navas-Enamorado I, Santos-Ocaña C, Hernández-Camacho JD, Guerra I, Cascajo MV, Sánchez-Cuesta A, Horvath Z, Siendones E, Jou-Munoz C, Casado-Rio M, Gutiérrez P, Brea-Calvo G, López-Lluch G, Fernández-Ayala DJM, Cortés-Rodríguez AB, Rodríguez-Aguilera JC, Matté C, Ribes A, Prieto-Soler SY, Dominguez-Del-Toro E, Francesco AD, Aon MA, Bernier M, Salviati L, Artuch-Iriberri R, Cabo R, Jackson S and Navas P
Publicada:
1 sep 2019
Ahead of Print:
2 sep 2019
Categoría:
Medicine (miscellaneous)
Resumen:
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 Adck2+/- 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.
Filiaciones:
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-Munoz 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-Rio 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-Iriberri 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.
CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain.
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