Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I

Etienne Galemou Yoga,Amina Djurabekova,Volker Zickermann,Vivek Sharma,Kristian Parey,Heike Angerer,Klaus Zwicker,Karin Siegmund,Outi Haapanen

doi:10.1038/s41467-020-19778-7

Abstract

Respiratory complex I catalyzes electron transfer from NADH to ubiquinone (Q) coupled to vectorial proton translocation across the inner mitochondrial membrane. Despite recent progress in structure determination of this very large membrane protein complex, the coupling mechanism is a matter of ongoing debate and the function of accessory subunits surrounding the canonical core subunits is essentially unknown. Concerted rearrangements within a cluster of conserved loops of central subunits NDUFS2 (β1-β2S2 loop), ND1 (TMH5-6ND1 loop) and ND3 (TMH1-2ND3 loop) were suggested to be critical for its proton pumping mechanism. Here, we show that stabilization of the TMH1-2ND3 loop by accessory subunit LYRM6 (NDUFA6) is pivotal for energy conversion by mitochondrial complex I. We determined the high-resolution structure of inactive mutant F89ALYRM6 of eukaryotic complex I from the yeast Yarrowia lipolytica and found long-range structural changes affecting the entire loop cluster. In atomistic molecular dynamics simulations of the mutant, we observed conformational transitions in the loop cluster that disrupted a putative pathway for delivery of substrate protons required in Q redox chemistry. Our results elucidate in detail the essential role of accessory subunit LYRM6 for the function of eukaryotic complex I and offer clues on its redox-linked proton pumping mechanism.

Highlights

Respiratory complex I catalyzes electron transfer from NADH to ubiquinone (Q) coupled to vectorial proton translocation across the inner mitochondrial membrane
A substantial decrease of Q reductase activity was caused by exchange of LYRM6 residues interacting with residues in central subunits NDUFS2 (W90ALYRM6) and NDUFS7 (Q92ALYRM6) and accessory subunit NDUFA9 (E44ALYRM6)
These residues reside in the center of the accessory LYRM6 loop arrangement that interacts with a short section (L42-T43-S44ND3) of the TMH1-2ND3 loop that is downstream to the functionally highly critical and conserved E39-C40-G41ND3 segment (Fig. 1 inset, Supplementary Fig. 2)

Summary

Introduction

Respiratory complex I catalyzes electron transfer from NADH to ubiquinone (Q) coupled to vectorial proton translocation across the inner mitochondrial membrane. The LYRM6-ACPM heterodimer binds close to the functionally critical interface region of membrane and matrix arm of complex I (Fig. 1) and two adjacent loops of accessory LYRM6 interact with central subunits of mitochondrial complex I1.

Results

Conclusion