Novel COX11 Mutations Associated with Mitochondrial Disorder: Functional Characterization in Patient Fibroblasts and Saccharomyces cerevisiae.
Int J Mol Sci
; 24(23)2023 Nov 23.
Article
en En
| MEDLINE
| ID: mdl-38068960
Genetic defects in the nuclear encoded subunits and assembly factors of cytochrome c oxidase (mitochondrial complex IV) are very rare and are associated with a wide variety of phenotypes. Biallelic pathogenic variants in the COX11 protein were previously identified in two unrelated children with infantile-onset mitochondrial encephalopathies. Through comprehensive clinical, genetic and functional analyses, here we report on a new patient harboring novel heterozygous variants in COX11, presenting with Leigh-like features, and provide additional experimental evidence for a direct correlation between COX11 protein expression and sensitivity to oxidative stress. To sort out the contribution of the single mutations to the phenotype, we employed a multi-faceted approach using Saccharomyces cerevisiae as a genetically manipulable system, and in silico structure-based analysis of human COX11. Our results reveal differential effects of the two novel COX11 mutations on yeast growth, respiration, and cellular redox status, as well as their potential impact on human protein stability and function. Strikingly, the functional deficits observed in patient fibroblasts are recapitulated in yeast models, validating the conservation of COX11's role in mitochondrial integrity across evolutionarily distant organisms. This study not only expands the mutational landscape of COX11-associated mitochondrial disorders but also underscores the continued translational relevance of yeast models in dissecting complex molecular pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Mitocondriales
/
Proteínas de Saccharomyces cerevisiae
Límite:
Child
/
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2023
Tipo del documento:
Article
País de afiliación:
Canadá