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

Autor: Andrea Di Francesco, Guillermo López-Lluch, Rafael de Cabo, Ignacio Guerra, Antonia Ribes, Sandra Y. Prieto-Soler, Ana Cortés, Luis Vazquez-Fonseca, Eduardo Domínguez-del-Toro, Cristina Jou, Miguel A. Aon, Sandra Jackson, Rafael Artuch, Zoltan Horvath, Juan Carlos Rodríguez-Aguilera, Jochen Schaefer, Ana Sánchez-Cuesta, Michel Bernier, Plácido Navas, María V. Cascajo, Daniel J. M. Fernández-Ayala, Gloria Brea-Calvo, Cristiane Matté, Emilio Siendones, Carlos Santos-Ocaña, Ignacio Navas-Enamorado, Purificación Gutierrez-Rios, Juan Diego Hernández-Camacho, Leonardo Salviati, Mercedes Casado
Přispěvatelé: Ministerio de Sanidad (España), Instituto de Salud Carlos III, Junta de Andalucía, Istituto di Ricerca Pediatrica Città della Speranza, National Institutes of Health (US)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
medicine.medical_specialty
Mitochondrial disease
Myopathy
respiratory chain
Respiratory chain
lcsh:Medicine
Coenzyme Q Deficiency
Biology
fatty acids
Article
medicine_pharmacology_other
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Mitochondrial myopathy
Lipid oxidation
Lipid droplet
Internal medicine
medicine
Coenzyme Q deficiency
aarF domain-containing mitochondrial protein kinase 2(ADCK2)
mitochondrial disease
myopathy
Fatty acids
Beta oxidation
030304 developmental biology
0303 health sciences
Fatty acid metabolism
business.industry
lcsh:R
CoQ Deficiency
General Medicine
medicine.disease
Endocrinology
AarF domain-containing mitochondrial protein kinase 2(ADCK2)
chemistry
medicine.symptom
Coenzyme Q deficiency
aarF domain-containing mitochondrial protein kinase 2(ADCK2)
fatty acids
mitochondrial disease
myopathy
respiratory chain
business
Haploinsufficiency
030217 neurology & neurosurgery
Zdroj: Journal of Clinical Medicine
Volume 8
Issue 9
Digital.CSIC. Repositorio Institucional del CSIC
instname
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
Fundació Sant Joan de Déu
Journal of Clinical Medicine, Vol 8, Iss 9, p 1374 (2019)
ISSN: 2077-0383
DOI: 10.3390/jcm8091374
Popis: © 2019 by the authors.
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.
This research was supported by grants from the Spanish Ministry of Health, Instituto de Salud Carlos III (ISCIII), PI17/01286 and Andalussian Government Excellence grant P12-CTS-943 to P.N., FIS PI17/00190 to R.A., by grants from Istituto di Ricerca Pediatrica Città della Speranza and Telethon Italy (GGP13222 and GGP14187c) to L.S., and the Intramural Research Program of National Institute on Aging, National Institutes of Health (NIA/NIH) (M.A.A., M.B. and R.d.C.). L.V.-F. doctoral thesis was directed by C.S.-O. I.N.-E. and A.d.F. were postdoctoral fellows at National Institute on Aging, National Institutes of Health (NIA/NIH).
Databáze: OpenAIRE
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