2025/11/05 by Olatz Ugarteburu, Laia Farré-Tarrats, Gerard Muñoz‐Pujol +14 · 1 voice
Biochemistry, Genetics and Molecular Biology · #ATP Synthase and ATPases Research #Mitochondrial Function and Pathology #Protein Tyrosine Phosphatases
paper · doi:10.1016/j.mito.2025.102095
openalex created_date 2025/11/05 · openalex publication_date 2025/11/05 · openalex updated_date 2026/08/01
• COX4I1 variants are associated with progressive motor deterioration, intellectual disability and Leigh syndrome. • Phasing of a de novo COX4I1 variant was resolved using long-read sequencing, highlighting its utility in complex genetic diagnoses. • Functional studies in COX4I1-deficient fibroblasts revealed a pathomechanism affecting both complex IV function and mitoribosomal protein levels. COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient’s tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV. Additionally, proteomic data in patient’s fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.