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The coupling mechanism of mammalian mitochondrial complex I.

Gu J, Liu T, Guo R, Zhang L, Yang M
Nat Struct Mol Biol 29 172-182 (2022)

Cited: 26 times
EuropePMC logo PMID: 35145322

Abstract

Mammalian respiratory complex I (CI) is a 45-subunit, redox-driven proton pump that generates an electrochemical gradient across the mitochondrial inner membrane to power ATP synthesis in mitochondria. In the present study, we report cryo-electron microscopy structures of CI from Sus scrofa in six treatment conditions at a resolution of 2.4-3.5 Å, in which CI structures of each condition can be classified into two biochemical classes (active or deactive), with a notably higher proportion of active CI particles. These structures illuminate how hydrophobic ubiquinone-10 (Q10) with its long isoprenoid tail is bound and reduced in a narrow Q chamber comprising four different Q10-binding sites. Structural comparisons of active CI structures from our decylubiquinone-NADH and rotenone-NADH datasets reveal that Q10 reduction at site 1 is not coupled to proton pumping in the membrane arm, which might instead be coupled to Q10 oxidation at site 2. Our data overturn the widely accepted previous proposal about the coupling mechanism of CI.

Reviews citing this publication (4)

  1. Structure of respiratory complex I - An emerging blueprint for the mechanism. Kampjut D, Sazanov LA. Curr Opin Struct Biol 74 102350 (2022)
  2. Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs. Tragni V, Primiano G, Tummolo A, Cafferati Beltrame L, La Piana G, Sgobba MN, Cavalluzzi MM, Paterno G, Gorgoglione R, Volpicella M, Guerra L, Marzulli D, Servidei S, De Grassi A, Petrosillo G, Lentini G, Pierri CL. Molecules 27 3494 (2022)
  3. Making the leap from structure to mechanism: are the open states of mammalian complex I identified by cryoEM resting states or catalytic intermediates? Chung I, Grba DN, Wright JJ, Hirst J. Curr Opin Struct Biol 77 102447 (2022)
  4. Binding of Natural Inhibitors to Respiratory Complex I. Schiller J, Zickermann V. Pharmaceuticals (Basel) 15 1088 (2022)

Articles citing this publication (22)

  1. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. Bridges HR, Blaza JN, Yin Z, Chung I, Pollak MN, Hirst J. Science 379 351-357 (2023)
  2. Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum. Laube E, Meier-Credo J, Langer JD, Kühlbrandt W. Sci Adv 8 eadc9952 (2022)
  3. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy. Chung I, Wright JJ, Bridges HR, Ivanov BS, Biner O, Pereira CS, Arantes GM, Hirst J. Nat Commun 13 2758 (2022)
  4. Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster. Agip AA, Chung I, Sanchez-Martinez A, Whitworth AJ, Hirst J. Elife 12 e84424 (2023)
  5. Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli. Zhang F, Dang QL, Vik SB. Mitochondrion 64 59-72 (2022)
  6. Quinone Catalysis Modulates Proton Transfer Reactions in the Membrane Domain of Respiratory Complex I. Kim H, Saura P, Pöverlein MC, Gamiz-Hernandez AP, Kaila VRI. J Am Chem Soc 145 17075-17086 (2023)
  7. Structure of mycobacterial respiratory complex I. Liang Y, Plourde A, Bueler SA, Liu J, Brzezinski P, Vahidi S, Rubinstein JL. Proc Natl Acad Sci U S A 120 e2214949120 (2023)
  8. Subunits E-F-G of E. coli Complex I can form an active complex when expressed alone, but in time-delayed assembly co-expression of B-CD-E-F-G is optimal. Alkhaldi HA, Vik SB. Biochim Biophys Acta Bioenerg 1863 148593 (2022)
  9. A universal coupling mechanism of respiratory complex I. Kravchuk V, Petrova O, Kampjut D, Wojciechowska-Bason A, Breese Z, Sazanov L. Nature 609 808-814 (2022)
  10. Analysis of Human Clinical Mutations of Mitochondrial ND1 in a Bacterial Model System for Complex I. Alkhaldi HA, Phan DH, Vik SB. Life (Basel) 12 1934 (2022)
  11. H2O2 selectively damages the binuclear iron-sulfur cluster N1b of respiratory complex I. Strotmann L, Harter C, Gerasimova T, Ritter K, Jessen HJ, Wohlwend D, Friedrich T. Sci Rep 13 7652 (2023)
  12. Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I. Zdorevskyi O, Djurabekova A, Lasham J, Sharma V. Chem Sci 14 6309-6318 (2023)
  13. Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I. Grba DN, Chung I, Bridges HR, Agip AA, Hirst J. Sci Adv 9 eadi1359 (2023)
  14. Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility. Pereira CS, Teixeira MH, Russell DA, Hirst J, Arantes GM. Sci Rep 13 6738 (2023)
  15. Mitochondria-targeting Cu3VS4 nanostructure with high copper ionic mobility for photothermoelectric therapy. Dong Y, Dong S, Yu C, Liu J, Gai S, Xie Y, Zhao Z, Qin X, Feng L, Yang P, Zhao Y. Sci Adv 9 eadi9980 (2023)
  16. Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I. Yi JT, Wang P, Stuchebrukhov AA. Sci Rep 13 20413 (2023)
  17. Polystyrene nanoplastic exposure induces excessive mitophagy by activating AMPK/ULK1 pathway in differentiated SH-SY5Y cells and dopaminergic neurons in vivo. Huang Y, Liang B, Li Z, Zhong Y, Wang B, Zhang B, Du J, Ye R, Xian H, Min W, Yan X, Deng Y, Feng Y, Bai R, Fan B, Yang X, Huang Z. Part Fibre Toxicol 20 44 (2023)
  18. Respiratory complex I in mitochondrial membrane catalyzes oversized ubiquinones. Ikunishi R, Otani R, Masuya T, Shinzawa-Itoh K, Shiba T, Murai M, Miyoshi H. J Biol Chem 299 105001 (2023)
  19. Single protonation of the reduced quinone in respiratory complex I drives four-proton pumping. Stuchebrukhov AA, Hayashi T. FEBS Lett 597 237-245 (2023)
  20. Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse. Yin Z, Agip AA, Bridges HR, Hirst J. EMBO J 43 225-249 (2024)
  21. Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae. Han F, Hu Y, Wu M, He Z, Tian H, Zhou L. Nat Commun 14 2542 (2023)
  22. cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization. Signorile A, Pacelli C, Palese LL, Santeramo A, Roca E, Cocco T, De Rasmo D. Int J Mol Sci 23 9655 (2022)


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