biostudies-literatureJackson TDMito Foundatione2115566119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9060475biostudies-literatureUnknown119(13)SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the energy currency of cells. ATP generation within mitochondria is performed by five multisubunit complexes (complexes I to V), the assembly of which is an intricate process. Mutations in subunits of these complexes, or the suite of proteins that help them assemble, lead to a severe multisystem condition called mitochondrial disease. We show that SFXN4, a protein that causes mitochondrial disease when mutated, assists with the assembly of complex I. This finding explains why mutations in <i>SFXN4</i> cause mitochondrial disease and is surprising because SFXN4 belongs to a family of amino acid transporter proteins, suggesting that it has undergone a dramatic shift in Proceedings of the National Academy of Sciences of the United States of AmericaSideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.PMC9060475N/AMuellner-Wong LFujihara KMStait TCrameri JJPalmer CSSharpe AJRyan MTStroud DAStojanovski DFormosa LEFrazier AEHock DHThorburn DRJackson TDfalseSideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the energy currency of cells. ATP generation within mitochondria is performed by five multisubunit complexes (complexes I to V), the assembly of which is an intricate process. Mutations in subunits of these complexes, or the suite of proteins that help them assemble, lead to a severe multisystem condition called mitochondrial disease. We show that SFXN4, a protein that causes mitochondrial disease when mutated, assists with the assembly of complex I. This finding explains why mutations in <i>SFXN4</i> cause mitochondrial disease and is surprising because SFXN4 belongs to a family of amino acid transporter proteins, suggesting that it has undergone a dramatic shift in 2022-01-01T00:00:00Z2022 Mar2026-05-31T01:07:15.066Z2025-04-04T11:31:27.545ZS-EPMC90604753533365510.1073/pnas.2115566119