Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly

Abstract

NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix arm. Fourteen central subunits are conserved throughout species, while some 30 accessory subunits are typically found in eukaryotes. Complex I dysfunction is associated with mutations in the nuclear and mitochondrial genome, resulting in a broad spectrum of neuromuscular and neurodegenerative diseases. Accessory subunit NDUFS4 in the matrix arm is a hot spot for mutations causing Leigh or Leigh-like syndrome. In this review, we focus on accessory subunits of the matrix arm and discuss recent reports on the function of accessory subunit NDUFS4 and its interplay with NDUFS6, NDUFA12, and assembly factor NDUFAF2 in complex I assembly.

Keywords: Leigh syndrome; NADH dehydrogenase; assembly factor; mitochondrial disease; oxidative phosphorylation; respiratory chain.

Figure 1

Functional modules of complex I and accessory subunits of the matrix arm. (A) The central subunits of complex I are assigned to functional modules for NADH oxidation (N module, orange), ubiquinone reduction (Q module, green), and proton pumping (P module, cyan). (B) Accessory subunits of the matrix arm of human complex I (PDB ID: 5xtd) are shown in color, all other subunits are shown in gray. (C) Accessory subunits of the matrix arm of Y. lipolytica complex I (PDB ID: 6rfr; color code as in (B)); the sulfur transferase subunit ST1 is not part of the model; note that FV3 is not present in Y. lipolytica complex I.

Figure 2

Structure of complex I lacking NDUFS4 and of an assembly intermediate harboring assembly factor NDUFAF2. (A) Cryo-EM structure of Y. lipolytica complex I purified from ndufs4Δ strain (PDB ID: 6rfs); the red arrow indicates direction of view for (B) and (C). (B) Detail view on NDUFS4 in wild type Y. lipolytica complex I (PDB ID: 6rfr), direction of view (see (A)). (C) Same as (B) for ndufs4Δ mutant (PDB ID: 6rfs); FeS clusters N1b and N3 are solvent exposed. (D) Structure of complex I assembly intermediate purified from Y. lipolytica ndufs6Δ strain (PDB ID: 6rfq). The assembly intermediate harbors assembly factor NDUFAF2 and all subunits, except NDUFS6 and NDUFA12. For clarity, only NDUFAF2 and NDUFS4 are shown in color. The position of NDUFAF2 matches the position of NDUFA12 in wild type complex I.