Journal of Clinical Medicine (Sep 2019)
<i>ADCK2</i> Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency
- Luis Vázquez-Fonseca,
- Jochen Schäefer,
- Ignacio Navas-Enamorado,
- Carlos Santos-Ocaña,
- Juan D. Hernández-Camacho,
- Ignacio Guerra,
- María V. Cascajo,
- Ana Sánchez-Cuesta,
- Zoltan Horvath,
- Emilio Siendones,
- Cristina Jou,
- Mercedes Casado,
- Purificación Gutierrez-Rios,
- Gloria Brea-Calvo,
- Guillermo López-Lluch,
- Daniel J.M. Fernández-Ayala,
- Ana B. Cortés,
- Juan C. Rodríguez-Aguilera,
- Cristiane Matté,
- Antonia Ribes,
- Sandra Y. Prieto-Soler,
- Eduardo Dominguez-del-Toro,
- Andrea di Francesco,
- Miguel A. Aon,
- Michel Bernier,
- Leonardo Salviati,
- Rafael Artuch,
- Rafael de Cabo,
- Sandra Jackson,
- Plácido Navas
Affiliations
- Luis Vázquez-Fonseca
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Jochen Schäefer
- Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany
- Ignacio Navas-Enamorado
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Carlos Santos-Ocaña
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Juan D. Hernández-Camacho
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Ignacio Guerra
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- María V. Cascajo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Ana Sánchez-Cuesta
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Zoltan Horvath
- Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany
- Emilio Siendones
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Cristina Jou
- CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain
- Mercedes Casado
- CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain
- Purificación Gutierrez-Rios
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Gloria Brea-Calvo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Daniel J.M. Fernández-Ayala
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Ana B. Cortés
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Juan C. Rodríguez-Aguilera
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Cristiane Matté
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul. CEP 90035-003 Porto Alegre, RS, Brazil
- Antonia Ribes
- CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain
- Sandra Y. Prieto-Soler
- División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain
- Eduardo Dominguez-del-Toro
- División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain
- Andrea di Francesco
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA
- Miguel A. Aon
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA
- Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA
- Leonardo Salviati
- Clinical Genetics Unit, Department of Women and Children’s Health, University of Padova, and IRP Città della Speranza, 35100 Padova, Italy
- Rafael Artuch
- CIBERER, Instituto de Salud Carlos III, 28000 Madrid, Spain
- Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 20201, USA
- Sandra Jackson
- Department of Neurology, Carl Gustav Carus University Dresden, 01307 Dresden, Germany
- Plácido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- DOI
- https://doi.org/10.3390/jcm8091374
- Journal volume & issue
-
Vol. 8,
no. 9
p. 1374
Abstract
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.
Keywords
- Coenzyme Q deficiency
- mitochondrial disease
- respiratory chain
- fatty acids
- myopathy
- aarF domain-containing mitochondrial protein kinase 2(ADCK2)