2026-05-17T00:18:17Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/269912025-12-18T12:57:29Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Cabrera-Alarcón, José Luis author Rosa-Moreno, Marina author Sánchez-García, Lucía author Hernansanz-Agustín, Pablo author Jiménez-Gómez, Maria Concepción author Martínez, Fernando author Sánchez-Cabo, Fátima author Enríquez, José Antonio author 2025-09-10 The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease. Cell Genom. 2025 Sep 10;5(9):100945. 40614727 https://hdl.handle.net/20.500.12105/26991 OxPhos conservation score evolutionary drivers human variability mitochondrial DNA mtDNA oxidative phosphorylation Structural diversity and evolutionary constraints of oxidative phosphorylation.