Proton-Translocating NADH-Ubiquinone Oxidoreductase: Interaction with Artificial Electron Acceptors, Inhibitors, and Potential Medicines

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Jan 8

PMID 39769185

Authors

Vera G Grivennikova

Grigory V Gladyshev

Tatyana V Zharova

Vitaliy B Borisov

Affiliations

Soon will be listed here.

Abstract

Proton-translocating NADH-ubiquinone oxidoreductase (complex I) catalyzes the oxidation of NADH by ubiquinone accompanied by the transmembrane transfer of four protons, thus contributing to the formation of a proton motive force () across the coupling membranes of mitochondria and bacteria, which drives ATP synthesis in oxidative phosphorylation. In recent years, great progress has been achieved in resolving complex I structure by means of X-ray crystallography and high-resolution cryo-electron microscopy, which has led to the formulation of detailed hypotheses concerning the molecular mechanism of coupling of the redox reaction to vectorial proton translocation. To test and probe proposed mechanisms, a comprehensive study of complex I using other methods including molecular dynamics and a variety of biochemical studies such as kinetic and inhibitory analysis is required. Due to complex I being a major electron entry point for oxidative metabolism, various mutations of the enzyme lead to the development of severe pathologies and/or are associated with human metabolic disorders and have been well documented. This review examines current information on the structure and subunit composition of complex I of eukaryotes and prokaryotes, reactions catalyzed by this enzyme, and ways to regulate them. The review also discusses biomedical aspects related to the enzyme in light of recent findings.

References

Hinchliffe P, Carroll J, Sazanov L . Identification of a novel subunit of respiratory complex I from Thermus thermophilus. Biochemistry. 2006; 45(14):4413-20. DOI: 10.1021/bi0600998. View

Formosa L, Dibley M, Stroud D, Ryan M . Building a complex complex: Assembly of mitochondrial respiratory chain complex I. Semin Cell Dev Biol. 2017; 76:154-162. DOI: 10.1016/j.semcdb.2017.08.011. View

Zhou Y, Zou J, Xu J, Zhou Y, Cen X, Zhao Y . Recent advances of mitochondrial complex I inhibitors for cancer therapy: Current status and future perspectives. Eur J Med Chem. 2023; 251:115219. DOI: 10.1016/j.ejmech.2023.115219. View

Varghese F, Atcheson E, Bridges H, Hirst J . Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. Hum Mol Genet. 2015; 24(22):6350-60. PMC: 4614703. DOI: 10.1093/hmg/ddv344. View

Agip A, Chung I, Sanchez-Martinez A, Whitworth A, Hirst J . Cryo-EM structures of mitochondrial respiratory complex I from . Elife. 2023; 12. PMC: 9977279. DOI: 10.7554/eLife.84424. View

Jarman O, Hirst J . Membrane-domain mutations in respiratory complex I impede catalysis but do not uncouple proton pumping from ubiquinone reduction. PNAS Nexus. 2023; 1(5):pgac276. PMC: 9802314. DOI: 10.1093/pnasnexus/pgac276. View

Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C . Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. Science. 2015; 347(6217):44-9. DOI: 10.1126/science.1259859. View

Sazanov L . From the 'black box' to 'domino effect' mechanism: what have we learned from the structures of respiratory complex I. Biochem J. 2023; 480(5):319-333. PMC: 10212512. DOI: 10.1042/BCJ20210285. View

Yagi T, Matsuno-Yagi A . The proton-translocating NADH-quinone oxidoreductase in the respiratory chain: the secret unlocked. Biochemistry. 2003; 42(8):2266-74. DOI: 10.1021/bi027158b. View

10.

Milliken A, Kulkarni C, Brookes P . Acid enhancement of ROS generation by complex-I reverse electron transport is balanced by acid inhibition of complex-II: Relevance for tissue reperfusion injury. Redox Biol. 2020; 37:101733. PMC: 7527751. DOI: 10.1016/j.redox.2020.101733. View

11.

Walker J . The NADH:ubiquinone oxidoreductase (complex I) of respiratory chains. Q Rev Biophys. 1992; 25(3):253-324. DOI: 10.1017/s003358350000425x. View

12.

Euro L, Bloch D, Wikstrom M, Verkhovsky M, Verkhovskaya M . Electrostatic interactions between FeS clusters in NADH:ubiquinone oxidoreductase (Complex I) from Escherichia coli. Biochemistry. 2008; 47(10):3185-93. DOI: 10.1021/bi702063t. View

13.

Le Breton N, Wright J, Jones A, Salvadori E, Bridges H, Hirst J . Using Hyperfine Electron Paramagnetic Resonance Spectroscopy to Define the Proton-Coupled Electron Transfer Reaction at Fe-S Cluster N2 in Respiratory Complex I. J Am Chem Soc. 2017; 139(45):16319-16326. DOI: 10.1021/jacs.7b09261. View

14.

Mamedova A, Holt P, Carroll J, Sazanov L . Substrate-induced conformational change in bacterial complex I. J Biol Chem. 2004; 279(22):23830-6. DOI: 10.1074/jbc.M401539200. View

15.

Roth K, Mambetsariev I, Kulkarni P, Salgia R . The Mitochondrion as an Emerging Therapeutic Target in Cancer. Trends Mol Med. 2019; 26(1):119-134. PMC: 6938552. DOI: 10.1016/j.molmed.2019.06.009. View

16.

Vinogradov A, Grivennikova V . Oxidation of NADH and ROS production by respiratory complex I. Biochim Biophys Acta. 2015; 1857(7):863-71. DOI: 10.1016/j.bbabio.2015.11.004. View

17.

Verkhovskaya M, Belevich N, Euro L, Wikstrom M, Verkhovsky M . Real-time electron transfer in respiratory complex I. Proc Natl Acad Sci U S A. 2008; 105(10):3763-7. PMC: 2268814. DOI: 10.1073/pnas.0711249105. View

18.

Khaniya U, Gupta C, Cai X, Mao J, Kaur D, Zhang Y . Hydrogen bond network analysis reveals the pathway for the proton transfer in the E-channel of T. thermophilus Complex I. Biochim Biophys Acta Bioenerg. 2020; 1861(10):148240. DOI: 10.1016/j.bbabio.2020.148240. View

19.

Kampjut D, Sazanov L . The coupling mechanism of mammalian respiratory complex I. Science. 2020; 370(6516). DOI: 10.1126/science.abc4209. View

20.

Gladyshev G, Zharova T, Kareyeva A, Grivennikova V . Proton-translocating NADH:ubiquinone oxidoreductase of Paracoccus denitrificans plasma membranes catalyzes FMN-independent reverse electron transfer to hexaammineruthenium (III). Biochim Biophys Acta Bioenerg. 2023; 1864(2):148963. DOI: 10.1016/j.bbabio.2023.148963. View