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Novel COX11 Mutations Associated with Mitochondrial Disorder: Functional Characterization in Patient Fibroblasts and Saccharomyces cerevisiae

Authors :
Chenelle A. Caron-Godon
Stefania Della Vecchia
Alessandro Romano
Stefano Doccini
Flavio Dal Canto
Rosa Pasquariello
Anna Rubegni
Roberta Battini
Filippo Maria Santorelli
D. Moira Glerum
Claudia Nesti
Source :
International Journal of Molecular Sciences, Vol 24, Iss 23, p 16636 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
24
Issue :
23
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.b9810c181f33489dbe67343dcd693641
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms242316636