Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 3 August 2019 / Approved: 6 August 2019 / Online: 6 August 2019 (07:52:35 CEST)

A peer-reviewed article of this Preprint also exists.

Vázquez-Fonseca, L.; Schaefer, J.; Navas-Enamorado, I.; Santos-Ocaña, C.; Hernández-Camacho, J.D.; Guerra, I.; Cascajo, M.V.; Sánchez-Cuesta, A.; Horvath, Z.; Siendones, E.; Jou, C.; Casado, M.; Gutiérrez, P.; Brea-Calvo, G.; López-Lluch, G.; Fernández-Ayala, D.J.M.; Cortés-Rodríguez, A.B.; Rodríguez-Aguilera, J.C.; Matté, C.; Ribes, A.; Prieto-Soler, S.Y.; Dominguez-del-Toro, E.; Francesco, A.; Aon, M.A.; Bernier, M.; Salviati, L.; Artuch, R.; Cabo, R.; Jackson, S.; Navas, P. ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency. J. Clin. Med. 2019, 8, 1374. Vázquez-Fonseca, L.; Schaefer, J.; Navas-Enamorado, I.; Santos-Ocaña, C.; Hernández-Camacho, J.D.; Guerra, I.; Cascajo, M.V.; Sánchez-Cuesta, A.; Horvath, Z.; Siendones, E.; Jou, C.; Casado, M.; Gutiérrez, P.; Brea-Calvo, G.; López-Lluch, G.; Fernández-Ayala, D.J.M.; Cortés-Rodríguez, A.B.; Rodríguez-Aguilera, J.C.; Matté, C.; Ribes, A.; Prieto-Soler, S.Y.; Dominguez-del-Toro, E.; Francesco, A.; Aon, M.A.; Bernier, M.; Salviati, L.; Artuch, R.; Cabo, R.; Jackson, S.; Navas, P. ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency. J. Clin. Med. 2019, 8, 1374.

Journal reference: J. Clin. Med. 2019, 8, 1374
DOI: 10.3390/jcm8091374

Abstract

Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. 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 show that Aldh2+/- mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in 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.

Subject Areas

coenzyme Q deficiency; mitochondrial disease; respiratory chain; fatty acids; myopathy; ADCK2

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