Binding of Natural Inhibitors to Respiratory Complex I

Abstract

NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a tunnel. A variety of chemically diverse compounds are known to inhibit ubiquinone reduction by complex I. Rotenone, piericidin A, and annonaceous acetogenins are representatives of complex I inhibitors from biological sources. The structure of complex I is determined at high resolution, and inhibitor binding sites are described in detail. In this review, we summarize the state of knowledge of how natural inhibitors bind in the Q reduction site and the Q access pathway and how their inhibitory mechanisms compare with that of a synthetic anti-cancer agent.

Keywords: NADH dehydrogenase; Parkinson’s disease; acetogenin; mitochondria; piericidin; respiratory chain; rotenone.

Figure 1

Complex I inhibitors and structural basis of Q binding and reduction. Chemical structures of (A) ubiquinone (Q10, n = 10), (B) piericidin A, (C) an annonaceous acetogenin, (D) rotenone, and (E) IACS-2858 (THF = tetrahydrofuran ring, THP = tetrahydropyran ring). (F) Architecture of respiratory complex I with NDUFS7 (blue), NDUFS2(green), and ND1 (pink), and the Q tunnel. The viewpoint is indicated and the section of the detail view in Figure 2 and Figure 3 is highlighted by a box. (G) Detail view of the Q reduction site and access pathway as shown in Figure 2 and Figure 3; a tyrosine and a histidine residue of NDUFS2 play a key role for binding the Q head group (compare Figure 2, residue numbers see Table 1, for details see text).

Figure 2

Q-binding sites in respiratory complex I. Q reduction site near FeS cluster N2 and access pathway for Q from the membrane with NDUFS7 (blue), NDUFS2 (green), and ND1 (pink) (compare Figure 1); Q molecules and residues discussed in the text are shown in stick representation (numbering see Table 1). (A) Q10 bound to complex I from B. taurus in lipid nanodisc (PDB ID 7QSK), (B) native Q9 in the Q access pathway of complex I from Y. lipolytica (PDB ID 6RFR), (C) head group of decyl benzoquinone (DBQ) bound to complex I from Y. lipolytica captured under turnover (PDB ID 7O6Y), and (D) DBQ bound to complex I from T. thermophilus (PDB ID 6I0D).

Figure 3

Binding of natural inhibitors and IACS-2858 to respiratory complex I. Q reduction site near FeS cluster N2 and access pathway as shown in Figure 2. (A) Piericidin A bound to complex I from M. musculus (PDB ID 6ZTQ), (B) two rotenone molecules bound to complex I from O. aries (PDB ID 6ZKN), (C) annonaceous acetogenin (compound 1 as described in Grba et al., 2022) bound to complex I from M. musculus (PDB ID 7PSA), and (D) the synthetic anti-cancer agent IACS-2858 bound to complex I from M. musculus (PDB ID 7B93); for residue numbering see Table 1.