Harhai, MarcellFoged, Mads M.Zarges, ChristineLandoni, Juan CruzChollet, SylvainSimonelli, MicheleRecazens, EmelineLisci, MiriamLaban, NoraManley, SulianaRiemer, JanLopez-Escamez, Jose AntonioLysakowski, AnnaJourdain, Alexis A.2025-08-202025-08-202025-08-192025-08-2610.1016/j.celrep.2025.116069https://infoscience.epfl.ch/handle/20.500.14299/253213WOS:00154246310000140714634Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Me<acute accent>nie`re's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Me<acute accent>nie`re's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.EnglishCLPBCP: MetabolismFAM136Afunctional genomicsHAX1intermembrane spacemitochondriamitochondrial diseaseMénièreOXPHOSproteostasistext::journal::journal article::research article