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

AuthorsVázquez-Fonseca, Luis; Schäefer, Jochen; Navas-Enamorado, Ignacio; Santos-Ocaña, Carlos ; Hernández-Camacho, Juan Diego; Guerra, Ignacio; Cascajo Almenara, M. V. ; Sánchez-Cuesta, Ana; Horvath, Zoltan; Siendones, Emilio ; Jou, Cristina; Casado, Mercedes; Gutierrez-Rios, Purificacion; Brea-Calvo, Gloria ; López-Lluch, Guillermo ; Fernández-Ayala, Daniel J. M.; Cortés-Rodríguez, Ana Belén; Rodríguez-Aguilera, Juan Carlos ; Matté, Cristiane; Ribes, Antonia; Prieto-Soler, Sandra Y.; Dominguez-del-Toro, Eduardo; Francesco, Andrea Di; Aon, Miguel A.; Bernier, Michel; Salviati, Leonardo; Artuch, Rafael; Cabo, Rafael de; Jackson, Sandra; Navas, Plácido
KeywordsCoenzyme Q deficiency
Mitochondrial disease
Respiratory chain
Fatty acids
AarF domain-containing mitochondrial protein kinase 2(ADCK2)
Issue Date2019
PublisherMultidisciplinary Digital Publishing Institute
CitationJournal of Clinical Medicine 8(9): 1374 (2019)
AbstractFatty 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.
Description© 2019 by the authors.
Publisher version (URL)http://dx.doi.org/10.3390/jcm8091374
Appears in Collections:(CABD) Artículos
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