RT Journal Article
T1 Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.
A1 Romero-Moya, Damià
A1 Santos-Ocaña, Carlos
A1 Castaño, Julio
A1 Garrabou, Gloria
A1 Rodríguez-Gómez, José A
A1 Ruiz-Bonilla, Vanesa
A1 Bueno, Clara
A1 González-Rodríguez, Patricia
A1 Giorgetti, Alessandra
A1 Perdiguero, Eusebio
A1 Prieto, Cristina
A1 Moren-Nuñez, Constanza
A1 Fernández-Ayala, Daniel J
A1 Victoria Cascajo, Maria
A1 Velasco, Iván
A1 Canals, Josep Maria
A1 Montero, Raquel
A1 Yubero, Delia
A1 Jou, Cristina
A1 López-Barneo, José
A1 Cardellach, Francesc
A1 Muñoz-Cánoves, Pura
A1 Artuch, Rafael
A1 Navas, Plácido
A1 Menendez, Pablo
K1 COQ4
K1 CRISPR-Cas9
K1 Coenzyme Q10
K1 Dopaminergic and motor neurons
K1 Induced pluripotent stem cell
K1 Skeletal muscle
AB 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.
YR 2017
FD 2017-05-23
LK http://hdl.handle.net/10668/11172
UL http://hdl.handle.net/10668/11172
LA en
DS RISalud
RD Apr 10, 2025