Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) assembly factors; NDUFAF1-8/NUBPL/FOXRED1/TIMMDC1

Biogenesis of respiratory Complex I (NADH:ubiquinone oxidoreductase) is the most factor-dependent of all OXPHOS assembly pathways: its ~45 subunits (7 mtDNA-encoded membrane ND subunits and ~38 nuclear-encoded) are built as preassembled modules (N/Q/ND1/ND2/ND4/ND5) that are then joined, and this ordered process requires at least a dozen dedicated assembly factors that are not part of the mature holoenzyme. This module groups the human Complex I assembly factors by the step they serve. The membrane-arm (MCIA) machinery — NDUFAF1 (CIA30) together with ACAD9/ECSIT/ TMEM126B (reviewed with the core) and the multi-pass insertase-like scaffold TIMMDC1 — builds the ND2/membrane intermediates. The Q-module/mid-stage intermediate is chaperoned by the NDUFAF3– NDUFAF4 pair and by NDUFAF6. A set of factors covalently modify or metallate specific core subunits before they can be incorporated: NDUFAF5 hydroxylates a conserved arginine of NDUFS7, NDUFAF7 symmetrically dimethylates an arginine of NDUFS2, NUBPL (IND1) delivers the [4Fe-4S] clusters, and the FAD-dependent oxidoreductase-fold protein FOXRED1 is required for maturation of the late ~815 kDa intermediate (its substrate, if any, is unknown). Finally the late N-module is stabilised by NDUFAF2 (NDUFA12L) — a paralogue of the structural subunit NDUFA12 that binds transiently and is released from the mature enzyme — together with NDUFAF8, which is imported by the MIA40 disulfide relay and cooperates with NDUFAF5. Loss of any of these factors causes mitochondrial complex I deficiency, the commonest inborn OXPHOS defect — Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, hypertrophic cardiomyopathy and encephalopathy.