Optic atrophy–associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I

Significance Mitochondria are critical organelles that play a central role in energy conversion in cells. Mutations in genes encoding mitochondrial proteins can lead to disease. Here, we discover that the optic atrophy–associated mitochondrial disease gene TMEM126A plays a role in the assembly of the first enzyme of the respiratory chain, complex I. Critically, we show that TMEM126A interacts in a complex with newly synthesized ND4, a highly hydrophobic subunit of complex I that is encoded by mitochondrial DNA. Our findings expand the molecular machinery required to build complex I from its constituent subunits and elucidates the function of a gene mutated in mitochondrial disease.