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

Etienne Galemou Yoga, Kristian Parey, Amina Djurabekova, Outi Haapanen, Karin Siegmund, Klaus Zwicker, Vivek Sharma (), Volker Zickermann and Heike Angerer ()
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Etienne Galemou Yoga: Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Goethe University
Kristian Parey: Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Goethe University
Amina Djurabekova: Department of Physics, P.O. Box 64, University of Helsinki
Outi Haapanen: Department of Physics, P.O. Box 64, University of Helsinki
Karin Siegmund: Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Goethe University
Klaus Zwicker: Medical School, Institute of Biochemistry I, Goethe University
Vivek Sharma: Department of Physics, P.O. Box 64, University of Helsinki
Volker Zickermann: Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Goethe University
Heike Angerer: Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Goethe University

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19778-7

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