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Stem Cells. 2017 Jul;35(7):1687-1703. doi: 10.1002/stem.2634. Epub 2017 May 23.

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.

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Josep Carreras Leukemia Research Institute, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
Centro Andaluz de Biología del Desarrollo, Universidad Pablo Olavide-CSIC, Sevilla, Spain.
CIBER de Enfermedades Raras (CIBERER), Spain.
Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS-Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío-Consejo Superior de Investigaciones Científicas (CSIC)-University of Seville, Seville, Spain.
CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.
Pompeu Fabra University (UPF), Barcelona, Spain.
Insituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, México.
Laboratorio de Reprogramación Celular del IFC en el Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", México DF, México.
Stem Cells and Regenerative Medicine Laboratory, Production and validation center of advanced therapies (Creatio) Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
Neuroscience Institute, University of Barcelona, Barcelona, Spain.
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Clinical Biochemistry Department, Pediatric Research Institute-Hospital Sant Joan de Déu, Barcelona, Spain.
Institució Catalana Recerca Estudis Avančats (ICREA), Lluís Companys 23, Barcelona, Spain.
Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), ISCIII, Spain.


Coenzyme Q10 (CoQ10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ10 biosynthesis (COQ genes) cause primary CoQ10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ10 ], CoQ10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4ed -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687-1703.


COQ4; CRISPR-Cas9; Coenzyme Q10; Dopaminergic and motor neurons; Induced pluripotent stem cell; Skeletal muscle

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