Cabrera-Alarcón, José LuisRosa-Moreno, MarinaSánchez-García, LucíaHernansanz-Agustín, PabloJiménez-Gómez, Maria ConcepciónMartínez, FernandoSánchez-Cabo, FátimaEnríquez, José Antonio2025-12-092025-12-092025-09-10Cell Genom. 2025 Sep 10;5(9):100945.https://hdl.handle.net/20.500.12105/26991The 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.We thank M.M. Mun˜ oz-Hernandez, R. Martı´nez de Mena, and E.R. Martı´nez Jime´ nez for technical assistance. J.A.E. is supported by Human Frotier Science Program (RGP0016/2018), RTI2018-099357-B-I00, PID2021-1279880B, and TED2021-131611B-I00 funded by MCIN/AEI/10.13039/501100011033 and the European Union ‘‘NextGenerationEU’’/Plan de Recuperacio´ n Transformacio´ n y Resiliencia/PRTR, CIBERFES (CB16/10/00282). J.L.C.-A. is supported by Fundacio´ n ‘‘la Caixa’’ (LCF/PR/HR23/52430010). P.H.-A. is supported by JDC IJC2020-042679-I. M.R.-M. is supported by a ‘‘Severo Ochoa’’ FPI Fellowship (PRE2021-097721) awarded by MICIU/AEI/10.13039/50110001 1033 and by European Social Funds (FSE invierte en tu futuro). F.S.-C. is supported by TED2021-131611B-I00 and EQC2021-007294-P funded by MCIN/AEI/10.13039/501100011033 and the European Union ‘‘NextGenerationEU’’/ Plan de Recuperacio´ n Transformacio´ n y Resiliencia/PRTR and by CIBERCV (CB22/11/00021). L.S.-G. is supported by PTA2020-019067-I MICIU/AEI/ 10.13039/501100011033. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacio´ n y Universidades (MICIU), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/OxPhosconservation scoreevolutionary drivershuman variabilitymitochondrial DNAmtDNAoxidative phosphorylationAttribution-NonCommercial-NoDerivatives 4.0 International406147275(9)100945.open access