Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH

Marta Vranas, Daniel Wohlwend, Danye Qiu, Stefan Gerhardt, Christian Trncik, Mehrosh Pervaiz, Kevin Ritter, Stefan Steimle, Antonio Randazzo, Oliver Einsle, Stefan Günther, Henning J. Jessen, Alexander Kotlyar*, Thorsten Friedrich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH-OH specifically blocks NADH oxidation and ROS production by complex I in nanomolar concentrations. Attempts to elucidate its structure by NMR spectroscopy have failed. Here, by using X-ray crystallographic analysis, we report the structure of NADH-OH bound in the active site of a soluble fragment of complex I at 2.0 Å resolution. We have identified key amino acid residues that are specific and essential for binding NADH-OH. Furthermore, the structure sheds light on the specificity of NADH-OH towards the unique Rossmann-fold of complex I and indicates a regulatory role in mitochondrial ROS generation. In addition, NADH-OH acts as a lead-structure for the synthesis of a novel class of ROS suppressors.

Original languageEnglish
Pages (from-to)27277-27281
Number of pages5
JournalAngewandte Chemie - International Edition
Volume60
Issue number52
DOIs
StatePublished - 20 Dec 2021

Funding

FundersFunder number
Deutsche Forschungsgemeinschaft278002225/RTG 2202, FR 1140/11‐2, SPP1927
Volkswagen Foundation6SAQ

    Keywords

    • NADH:ubiquinone oxidoreductase
    • electron transport
    • inhibitors
    • reactive oxygen species
    • structural biology

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