FAM136A is an essential chaperone for mitochondrial membrane protein biogenesis
Ernst, M.; Zhang, J.; Xu, H.; Ma, A.; Boegeholz, L. A. K.; Szabo, M.; Wang, T.-Y.; Chou, T.-F.; Guna, A.; Voorhees, R. M.
Show abstract
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 {beta}-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 -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.
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