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

doi:10.1002/anie.202112165

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

Biochemistry Molecular Biology

Research output: Contribution to journal › Article › peer-review

11 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 language	English
Pages (from-to)	27277-27281
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	60
Issue number	52
DOIs	https://doi.org/10.1002/anie.202112165
State	Published - 20 Dec 2021

Keywords

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

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10.1002/anie.202112165

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Vranas, M., Wohlwend, D., Qiu, D., Gerhardt, S., Trncik, C., Pervaiz, M., Ritter, K., Steimle, S., Randazzo, A., Einsle, O., Günther, S., Jessen, H. J., Kotlyar, A., & Friedrich, T. (2021). Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH. Angewandte Chemie - International Edition, 60(52), 27277-27281. https://doi.org/10.1002/anie.202112165

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title = "Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH",

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 {\AA} 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.",

keywords = "NADH:ubiquinone oxidoreductase, electron transport, inhibitors, reactive oxygen species, structural biology",

author = "Marta Vranas and Daniel Wohlwend and Danye Qiu and Stefan Gerhardt and Christian Trncik and Mehrosh Pervaiz and Kevin Ritter and Stefan Steimle and Antonio Randazzo and Oliver Einsle and Stefan G{\"u}nther and Jessen, {Henning J.} and Alexander Kotlyar and Thorsten Friedrich",

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month = dec,

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doi = "10.1002/anie.202112165",

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Vranas, M, Wohlwend, D, Qiu, D, Gerhardt, S, Trncik, C, Pervaiz, M, Ritter, K, Steimle, S, Randazzo, A, Einsle, O, Günther, S, Jessen, HJ, Kotlyar, A & Friedrich, T 2021, 'Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH', Angewandte Chemie - International Edition, vol. 60, no. 52, pp. 27277-27281. https://doi.org/10.1002/anie.202112165

TY - JOUR

T1 - Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH

AU - Vranas, Marta

AU - Wohlwend, Daniel

AU - Qiu, Danye

AU - Gerhardt, Stefan

AU - Trncik, Christian

AU - Pervaiz, Mehrosh

AU - Ritter, Kevin

AU - Steimle, Stefan

AU - Randazzo, Antonio

AU - Einsle, Oliver

AU - Günther, Stefan

AU - Jessen, Henning J.

AU - Kotlyar, Alexander

AU - Friedrich, Thorsten

PY - 2021/12/20

Y1 - 2021/12/20

N2 - 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.

AB - 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.

KW - NADH:ubiquinone oxidoreductase

KW - electron transport

KW - inhibitors

KW - reactive oxygen species

KW - structural biology

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JF - Angewandte Chemie - International Edition

IS - 52

ER -

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

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