Dissecting the concordant and disparate roles of NDUFAF3 and NDUFAF4 in mitochondrial complex I biogenesis.

Distinct sub-assemblies (modules) of mitochondrial complex I (CI) are assembled with the assistance of CI Assembly Factors (CIAFs) through mechanisms that are incompletely defined. Here, using genetic analyses in , we report that when either of the CIAFs - NDUFAF3 or NDUFAF4 - is disrupted, biogenesis of the Q-, N-, and P-modules of CI is impaired. This is due, at least in part, to the compromised integration of NDUFS3 and NDUFS5 into the Q-, and P-modules, respectively, coupled with a destabilization of another CIAF, TIMMDC1, in assembly intermediates.