FAM136A is an essential chaperone for mitochondrial membrane protein biogenesis
The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins. Using a genome wide CRISPRi screen we found that in human cells FAM136A is required for biogenesis of all three voltage-dependent anion channel (VDAC) paralogs, an abundant and essential family of β-barrel metabolite transporters in the outer mitochondrial membrane (OM). FAM136A is a ubiquitously expressed essential gene, that is conserved in metazoa and plants. Using a combination of experiments in human cells and in vitro reconstitution, we determined that FAM136A associates with unfolded VDACs in the IMS; solubilizes nascent VDAC through a direct interaction; and facilitates insertion of VDAC into the OM. FAM136A also binds and chaperones a subset of α-helical subunits of the electron transport chain. We therefore conclude that FAM136A is an IMS-resident chaperone, necessary and sufficient to maintain nascent membrane proteins in a folding-competent state to mediate their integration into the bilayer.