ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Approval
2.2. Mouse Model
2.3. Cell Strains and Culture
2.4. Targeted Gene Sequencing
2.5. Measurement of Plasma Acyl-Carnitine and Urinary Organic Acids
2.6. Yeast Functional Complementation
2.7. Physical and Behavioral Tests
2.8. CoQ Determination and Biosynthesis
2.9. Mitochondrial Biochemistry
2.10. Microarray Analysis
2.11. Untargeted Metabolomics Assay
2.12. Metabolic Cages
2.13. Quantitative Real-Time PCR
2.14. ADCK2 Silencing by siRNA
2.15. Antibodies
2.16. Statistics
3. Results
3.1. Haploinsufficiency of Human ADCK2 Caused a Defect in Lipid Catabolism and CoQ10-Deficient Myopathy
3.2. A Heterozygous Adck2 Knockout Mouse Model Recapitulated the Phenotype Observed in Patient II-3
3.3. Adck2 Deficiency Caused CoQ Deficiency in MEFs and Skeletal Muscle
3.4. Adck2 Haploinsufficiency Caused Mitochondrial Dysfunction
3.5. Adck2 Haploinsufficiency Decreased Mitochondrial Fatty Acid β-Oxidation Required to Promote Cellular Growth
3.6. Adck2 Haploinsufficiency Affected the Gene Expression Profile in Muscle and Liver
3.7. Adck2 Haploinsufficiency Affected the Metabolomics Profile
3.8. CoQ Supplementation Partially Rescued the Adck2+/− Phenotype
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Vázquez-Fonseca, L.; Schäefer, J.; Navas-Enamorado, I.; Santos-Ocaña, C.; Hernández-Camacho, J.D.; Guerra, I.; Cascajo, M.V.; Sánchez-Cuesta, A.; Horvath, Z.; Siendones, E.; et al. ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency. J. Clin. Med. 2019, 8, 1374. https://doi.org/10.3390/jcm8091374
Vázquez-Fonseca L, Schäefer J, Navas-Enamorado I, Santos-Ocaña C, Hernández-Camacho JD, Guerra I, Cascajo MV, Sánchez-Cuesta A, Horvath Z, Siendones E, et al. ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency. Journal of Clinical Medicine. 2019; 8(9):1374. https://doi.org/10.3390/jcm8091374
Chicago/Turabian StyleVázquez-Fonseca, Luis, Jochen Schäefer, Ignacio Navas-Enamorado, Carlos Santos-Ocaña, Juan D. Hernández-Camacho, Ignacio Guerra, María V. Cascajo, Ana Sánchez-Cuesta, Zoltan Horvath, Emilio Siendones, and et al. 2019. "ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency" Journal of Clinical Medicine 8, no. 9: 1374. https://doi.org/10.3390/jcm8091374