Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Architecture of bacterial respiratory chains

Abstract

Bacteria power their energy metabolism using membrane-bound respiratory enzymes that capture chemical energy and transduce it by pumping protons or Na+ ions across their cell membranes. Recent breakthroughs in molecular bioenergetics have elucidated the architecture and function of many bacterial respiratory enzymes, although key mechanistic principles remain debated. In this Review, we present an overview of the structure, function and bioenergetic principles of modular bacterial respiratory chains and discuss their differences from the eukaryotic counterparts. We also discuss bacterial supercomplexes, which provide central energy transduction systems in several bacteria, including important pathogens, and which could open up possible avenues for treatment of disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Examples of bacterial respiratory chains.
Fig. 2: Structure and function of initial electron acceptors in bacterial respiratory chains.
Fig. 3: The bacterial complex III and its Q-cycle mechanism.
Fig. 4: Bacterial terminal respiratory oxidases.
Fig. 5: Bacterial respiratory supercomplexes.

Similar content being viewed by others

References

  1. Mitchell, P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191, 144–148 (1961). The basis of modern bioenergetics.

    Article  PubMed  CAS  Google Scholar 

  2. Borisov, V. B. et al. Aerobic respiratory chain of Escherichia coli is not allowed to work in fully uncoupled mode. Proc. Natl Acad. Sci. USA 108, 17320–17324 (2011).

    Article  PubMed  CAS  Google Scholar 

  3. Yoshida, M., Muneyuki, E. & Hisabori, T. ATP synthase: a marvellous rotary engine of the cell. Nat. Rev. Mol. Cell Biol. 2, 669–677 (2001).

    Article  PubMed  CAS  Google Scholar 

  4. Mulkidjanian, A. Y., Dibrov, P. & Galperin, M. Y. The past and present of sodium energetics: May the sodium-motive force be with you. Biochim. Biophys. Acta Bioenerg. 1777, 985–992 (2008). A concise review of bacterial sodium-motive force.

    Article  CAS  Google Scholar 

  5. Cook, G. M., Greening, C., Hards, K. & Berney, M. Energetics of pathogenic bacteria and opportunities for drug development. Adv. Microb. Physiol. 65, 1–62 (2014).

    Article  PubMed  CAS  Google Scholar 

  6. Jormakka, M., Byrne, B. & Iwata, S. Protonmotive force generation by a redox loop mechanism. FEBS Lett. 545, 25–30 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Jormakka, M., Törnroth, S., Byrne, B. & Iwata, S. Molecular basis of proton motive force generation: structure of formate dehydrogenase-N. Science 295, 1863–1868 (2002).

    Article  PubMed  Google Scholar 

  8. Kaila, V. R. I. Long-range proton-coupled electron transfer in biological energy conversion: towards mechanistic understanding of respiratory complex I. J. R. Soc. Interface 15, 20170916 (2018). Long-range pumping principles of complex I.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dimroth, P., Jockel, P. & Schmid, M. Coupling mechanism of the oxaloacetate decarboxylase Na+ pump. Biochim. Biophys. Acta Bioenerg. 1505, 1–14 (2001).

    Article  CAS  Google Scholar 

  10. Padan, E. & Schuldiner, S. Na+/H+ antiporters, molecular devices that couple the Na+ and H+ circulation in cells. J. Bioenerg. Biomembr. 25, 647–669 (1993).

    Article  PubMed  CAS  Google Scholar 

  11. Häse, C. C., Fedorova, N. D., Galperin, M. Y. & Dibrov, P. A. Sodium ion cycle in bacterial pathogens: evidence from cross-genome comparisons. Microbiol. Mol. Biol. Rev. 65, 353–370 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Haines, T. H. Anionic lipid headgroups as a proton-conducting pathway along the surface of membranes: a hypothesis. Proc. Natl Acad. Sci. USA 80, 160–164 (1983).

    Article  PubMed  CAS  Google Scholar 

  13. Lange, C., Nett, J. H., Trumpower, B. L. & Hunte, C. Specific roles of protein–phospholipid interactions in the yeast cytochrome bc1 complex structure. EMBO J. 20, 6591–6600 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Amdursky, N., Lin, Y., Aho, N. & Groenhof, G. Exploring fast proton transfer events associated with lateral proton diffusion on the surface of membranes. Proc. Natl Acad. Sci. USA 116, 2443–2451 (2019).

    Article  PubMed  CAS  Google Scholar 

  15. Sandén, T., Salomonsson, L., Brzezinski, P. & Widengren, J. Surface-coupled proton exchange of a membrane-bound proton acceptor. Proc. Natl Acad. Sci. USA 107, 4129–4134 (2010).

    Article  PubMed  Google Scholar 

  16. Wiseman, B. et al. Structure of a functional obligate complex III2IV2 respiratory supercomplex from Mycobacterium smegmatis. Nat. Struct. Mol. Biol. 25, 1128–1136 (2018). The molecular structure of a mycobacterial obligate supercomplex.

    Article  PubMed  CAS  Google Scholar 

  17. Gong, H. et al. An electron transfer path connects subunits of a mycobacterial respiratory supercomplex. Science 362, eaat8923 (2018). The molecular structure of a mycobacterial obligate supercomplex.

    Article  PubMed  Google Scholar 

  18. Sohlenkamp, C. & Geiger, O. Bacterial membrane lipids: diversity in structures and pathways. FEMS Microbiol. Rev. 40, 133–159 (2016).

    Article  PubMed  CAS  Google Scholar 

  19. Kaila, V. R. I., Verkhovsky, M. I. & Wikström, M. Proton-coupled electron transfer in cytochrome oxidase. Chem. Rev. 110, 7062–7081 (2010). A source of the key concepts of aerobic respiration.

    Article  PubMed  CAS  Google Scholar 

  20. Agmon, N. The Grotthuss mechanism. Chem. Phys. Lett. 244, 456–462 (1995).

    Article  CAS  Google Scholar 

  21. Nagle, J. F. & Morowitz, H. J. Molecular mechanisms for proton transport in membranes. Proc. Natl Acad. Sci. USA 75, 298–302 (1978).

    Article  PubMed  CAS  Google Scholar 

  22. Marcus, R. A. & Sutin, N. Electron transfers in chemistry and biology. Biochim. Biophys. Acta Bioenerg. 811, 265–322 (1985).

    Article  CAS  Google Scholar 

  23. Beratan, D. N., Onuchic, J. N., Winkler, J. R. & Gray, H. B. Electron-tunneling pathways in proteins. Science 258, 1740–1741 (1992). Breakthrough work on biological electron transfer.

    Article  PubMed  CAS  Google Scholar 

  24. Page, C. C., Moser, C. C., Chen, X. & Dutton, P. L. Natural engineering principles of electron tunnelling in biological oxidation–reduction. Nature 402, 47–52 (1999). Breakthrough work on the general concept of biological electron transfer.

    Article  PubMed  CAS  Google Scholar 

  25. Kaila, V. R. I., Johansson, M. P., Sundholm, D. & Wikström, M. Interheme electron tunneling in cytochrome c oxidase. Proc. Natl Acad. Sci. USA 107, 21470–21475 (2010).

    Article  PubMed  CAS  Google Scholar 

  26. Blumberger, J. Recent advances in the theory and molecular simulation of biological electron transfer reactions. Chem. Rev. 115, 11191–11238 (2015).

    Article  PubMed  CAS  Google Scholar 

  27. Hill, T. L. Free Energy Transduction and Biochemical Cycle Kinetics (Springer, 1989).

  28. Tran, Q. H. & Unden, G. Changes in the proton potential and the cellular energetics of Escherichia coli during growth by aerobic and anaerobic respiration or by fermentation. Eur. J. Biochem. 251, 538–543 (1998).

    Article  PubMed  CAS  Google Scholar 

  29. Walker, J. E. The ATP synthase: the understood, the uncertain and the unknown. Biochem. Soc. Trans. 41, 1–16 (2013).

    Article  PubMed  CAS  Google Scholar 

  30. Preiss, L. et al. Structure of the mycobacterial ATP synthase fo rotor ring in complex with the anti-TB drug bedaquiline. Sci. Adv. 1, e1500106–e1500109 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Guo, H., Suzuki, T. & Rubinstein, J. L. Structure of a bacterial ATP synthase. eLife 8, e43128 (2019). A recent summary of bacterial ATP synthases.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Schlegel, K., Leone, V., Faraldo-Gómez, J. D. & Müller, V. Promiscuous archaeal ATP synthase concurrently coupled to Na+ and H+ translocation. Proc. Natl Acad. Sci. USA 109, 947–952 (2012).

    Article  PubMed  CAS  Google Scholar 

  33. Hinkle, P. C. P/O ratios of mitochondrial oxidative phosphorylation. Biochim. Biophys. Acta Bioenerg. 1706, 1–11 (2005).

    Article  CAS  Google Scholar 

  34. Wikström, M. & Hummer, G. Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc. Natl Acad. Sci. USA 109, 4431–4436 (2012).

    Article  PubMed  Google Scholar 

  35. Petersen, J., Förster, K., Turina, P. & Gräber, P. Comparison of the H+/ATP ratios of the H+-ATP synthases from yeast and from chloroplast. Proc. Natl Acad. Sci. USA 109, 11150–11155 (2012).

    Article  PubMed  CAS  Google Scholar 

  36. Soga, N., Kimura, K., Kinosita, K., Yoshida, M. & Suzuki, T. Perfect chemomechanical coupling of FoF1-ATP synthase. Proc. Natl Acad. Sci. USA 114, 4960–4965 (2017).

    Article  PubMed  CAS  Google Scholar 

  37. Jones, A. J. Y., Blaza, J. N., Varghese, F. & Hirst, J. Respiratory complex I in Bos taurus and Paracoccus denitrificans pumps four protons across the membrane for every NADH oxidized. J. Biol. Chem. 292, 4987–4995 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Westerhoff, H. V., Hellingwerf, K. J. & Van Dam, K. Thermodynamic efficiency of microbial growth is low but optimal for maximal growth rate. Proc. Natl Acad. Sci. USA 80, 305–309 (1983).

    Article  PubMed  CAS  Google Scholar 

  39. England, J. L. Statistical physics of self-replication. J. Chem. Phys. 139, 121923 (2013).

    Article  PubMed  Google Scholar 

  40. Crofts, A. R. The cytochrome bc1 complex: function in the context of structure. Annu. Rev. Physiol. 66, 689–733 (2004). A central review on complex III.

    Article  PubMed  CAS  Google Scholar 

  41. Nowicka, B. & Kruk, J. Occurrence, biosynthesis and function of isoprenoid quinones. Biochim. Biophys. Acta Bioenerg. 1797, 1587–1605 (2010).

    Article  CAS  Google Scholar 

  42. Jones, R. W. & Garland, P. B. The function of ubiquinone and menaquinone in the respiratory chain of Escherichia coli. Functions of Quinones in Energy Conserving Systems. 465–476 (Academic, 1982).

  43. Yankovskaya, V. et al. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299, 700–704 (2003). Structure of E. coli complex II.

    Article  PubMed  CAS  Google Scholar 

  44. Calhoun, M. W., Oden, K. L., Gennis, R. B., de Mattos, M. J. & Neijssel, O. M. Energetic efficiency of Escherichia coli: effects of mutations in components of the aerobic respiratory chain. J. Bacteriol. 175, 3020–3025 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Hino, T. et al. Structural basis of biological N2O generation by bacterial nitric oxide reductase. Science 330, 1666–1670 (2010). The first resolved molecular structure of a bacterial NOR.

    Article  PubMed  CAS  Google Scholar 

  46. Matsumoto, Y. et al. Crystal structure of quinol-dependent nitric oxide reductase from Geobacillus stearothermophilus. Nat. Struct. Mol. Biol. 19, 238–245 (2012).

    Article  PubMed  CAS  Google Scholar 

  47. de Gier, J.-W. L. et al. The terminal oxidases of Paracoccus denitrificans. Mol. Microbiol. 13, 183–196 (1994).

    Article  PubMed  Google Scholar 

  48. Puustinen, A., Finel, M., Virkki, M. & Wikström, M. Cytochrome o (bo) is a proton pump in Paracoccus denitrificans and Escherichia coli. FEBS Lett. 249, 163–167 (1989). A first account of proton pumping by bacterial oxidases.

    Article  PubMed  CAS  Google Scholar 

  49. Verkhovskaya, M. L. et al. Glutamic acid 286 in subunit I of cytochrome bo3 is involved in proton translocation. Proc. Natl Acad. Sci. USA 94, 10128–10131 (1997).

    Article  PubMed  CAS  Google Scholar 

  50. Borisov, V. B., Gennis, R. B., Hemp, J. & Verkhovsky, M. I. The cytochrome bd respiratory oxygen reductases. Biochim. Biophys. Acta 1807, 1398–1413 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bekker, M., de Vries, S., Ter Beek, A., Hellingwerf, K. J. & de Mattos, M. J. Respiration of Escherichia coli can be fully uncoupled via the nonelectrogenic terminal cytochrome bd-II oxidase. J. Bacteriol. 191, 5510–5517 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Kerscher, S., Dröse, S., Zickermann, V. & Brandt, U. The three families of respiratory NADH dehydrogenases. Results Probl. Cell Differ. 45, 185–222 (2008).

    Article  PubMed  CAS  Google Scholar 

  53. Melo, A. M. P., Bandeiras, T. M. & Teixeira, M. New insights into type II NAD(P)H:quinone oxidoreductases. Microbiol. Mol. Biol. Rev. 68, 603–616 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Bogachev, A., Murtazina, R. A. & Skulachev, V. P. The Na+/e- stoichiometry of the Na+-motive NADH: quinone oxidoreductase in Vibrio alginolyticus. FEBS Lett. 409, 475–477 (1997).

    Article  PubMed  CAS  Google Scholar 

  55. Verkhovsky, M. I. & Bogachev, A. V. Sodium-translocating NADH:quinone oxidoreductase as a redox-driven ion pump. Biochim. Biophys. Acta Bioenerg. 1797, 738–746 (2010).

    Article  CAS  Google Scholar 

  56. Hirst, J. Mitochondrial complex I. Annu. Rev. Biochem. 82, 551–575 (2013).

    Article  PubMed  CAS  Google Scholar 

  57. Brandt, U. Energy converting NADH: ubiquinone oxidoreductase (complex I). Annu. Rev. Biochem. 75, 69–92 (2006).

    Article  PubMed  CAS  Google Scholar 

  58. Sazanov, L. A. A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat. Rev. Mol. Cell Biol. 16, 375–388 (2015).

    Article  PubMed  CAS  Google Scholar 

  59. Baradaran, R., Berrisford, J. M., Minhas, G. S. & Sazanov, L. A. Crystal structure of the entire respiratory complex I. Nature 494, 443–448 (2013). The first complete molecular structure of bacterial complex I.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ohnishi, T. Iron-sulfur clusters/semiquinones in complex I. Biochim. Biophys. Acta Bioenerg. 1364, 186–206 (1998).

    Article  CAS  Google Scholar 

  61. Hunte, C., Zickermann, V. & Brandt, U. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329, 448–451 (2010).

    Article  PubMed  CAS  Google Scholar 

  62. Verkhovskaya, M. L., Belevich, N., Euro, L. & Wikström, M. Real-time electron transfer in respiratory complex I. Proc. Natl Acad. Sci. USA 105, 3763–3767 (2008).

    Article  PubMed  CAS  Google Scholar 

  63. Lambert, A. J. & Brand, M. D. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem. J. 382, 511–517 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zickermann, V. et al. Mechanistic insight from the crystal structure of mitochondrial complex I. Science 347, 44–49 (2015).

    Article  PubMed  CAS  Google Scholar 

  65. Brandt, U. Adaptations of an ancient modular machine. Science 363, 230–231 (2019).

    Article  PubMed  CAS  Google Scholar 

  66. Yu, H. et al. Structure of an ancient respiratory system. Cell 173, 1636–1649.e16 (2018). The first structure of an archaeal membrane-bound hydrogenase.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Olson, J. W. & Maier, R. J. Molecular hydrogen as an energy source for Helicobacter pylori. Science 298, 1788–1790 (2002).

    Article  PubMed  CAS  Google Scholar 

  68. Schuller, J. M. et al. Redox-coupled proton pumping drives carbon concentration in the photosynthetic complex I. Nat. Commun. 11, 494 (2020). Molecular adaptations enabling cyanobacterial carbon concentration.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Schuller, J. M. et al. Structural adaptations of photosynthetic complex I enable ferredoxin-dependent electron transfer. Science 363, 257–260 (2019).

    Article  PubMed  CAS  Google Scholar 

  70. Laughlin, T. G., Bayne, A. N., Trempe, J. F., Savage, D. F. & Davies, K. M. Structure of the complex I-like molecule NDH of oxygenic photosynthesis. Nature 566, 411–414 (2019).

    Article  PubMed  Google Scholar 

  71. Pan, X. et al. Structural basis for electron transport mechanism of complex I-like photosynthetic NAD(P)H dehydrogenase. Nat. Commun. 11, 610 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Di Luca, A., Gamiz-Hernandez, A. P. & Kaila, V. R. I. Symmetry-related proton transfer pathways in respiratory complex I. Proc. Natl Acad. Sci. USA 114, E6314–E6321 (2017).

    PubMed  Google Scholar 

  73. Sharma, V. et al. Redox-induced activation of the proton pump in the respiratory complex I. Proc. Natl Acad. Sci. USA 112, 11571–11576 (2015).

    Article  PubMed  CAS  Google Scholar 

  74. Euro, L., Belevich, G., Verkhovsky, M. I., Wikström, M. & Verkhovskaya, M. Conserved lysine residues of the membrane subunit NuoM are involved in energy conversion by the proton-pumping NADH:ubiquinone oxidoreductase (complex I). Biochim. Biophys. Acta 1777, 1166–1172 (2008).

    Article  PubMed  CAS  Google Scholar 

  75. Sena, F. V. et al. Type-II NADH:quinone oxidoreductase from Staphylococcus aureus has two distinct binding sites and is rate limited by quinone reduction. Mol. Microbiol. 98, 272–288 (2015).

    Article  PubMed  CAS  Google Scholar 

  76. Feng, Y. et al. Structural insight into the type-II mitochondrial NADH dehydrogenases. Nature 491, 478–482 (2012).

    Article  PubMed  CAS  Google Scholar 

  77. Iwata, M. et al. The structure of the yeast NADH dehydrogenase (Ndi1) reveals overlapping binding sites for water- and lipid-soluble substrates. Proc. Natl Acad. Sci. USA 109, 15247–15252 (2012).

    Article  PubMed  CAS  Google Scholar 

  78. Harbut, M. B. et al. Small molecules targeting mycobacterium tuberculosis type II NADH dehydrogenase exhibit antimycobacterial activity. Angew. Chem. Int. Ed. 57, 3478–3482 (2018).

    Article  CAS  Google Scholar 

  79. Steuber, J. et al. Structure of the V. cholerae Na+-pumping NADH:quinone oxidoreductase. Nature 516, 62–77 (2014).

    Article  PubMed  CAS  Google Scholar 

  80. Belevich, N. P., Bertsova, Y. V., Verkhovskaya, M. L., Baykov, A. A. & Bogachev, A. V. Identification of the coupling step in Na+-translocating NADH:quinone oxidoreductase from real-time kinetics of electron transfer. Biochim. Biophys. Acta 1857, 141–149 (2016).

    Article  PubMed  CAS  Google Scholar 

  81. Kurisu, G., Zhang, H., Smith, J. L. & Cramer, W. A. Structure of the cytochrome b6f complex of oxygenic photosynthesis: tuning the cavity. Science 302, 1009–1014 (2003).

    Article  PubMed  CAS  Google Scholar 

  82. Mitchell, P. Possible molecular mechanisms of the protonmotive function of cytochrome systems. J. Theor. Biol. 62, 327–367 (1976).

    Article  PubMed  CAS  Google Scholar 

  83. Kao, W. C. & Hunte, C. The molecular evolution of the Qo motif. Genome Biol. Evol. 7, 1894–1910 (2014).

    Article  Google Scholar 

  84. Sousa, J. S. et al. Structural basis for energy transduction by respiratory alternative complex III. Nat. Commun. 9, 1728–1728 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Majumder, E. L. W., King, J. D. & Blankenship, R. E. Alternative complex III from phototrophic bacteria and its electron acceptor auracyanin. Biochim. Biophys. Acta. Bioenerg. 1827, 1383–1391 (2013).

    Article  CAS  Google Scholar 

  86. Sun, C. et al. Structure of the alternative complex III in a supercomplex with cytochrome oxidase. Nature 557, 123–126 (2018). Structure of a bacterial supercomplex.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Alvarez-Paggi, D. et al. Multifunctional cytochrome c: learning new tricks from an old dog. Chem. Rev. 117, 13382–13460 (2017).

    Article  PubMed  CAS  Google Scholar 

  88. Kao, W. C. et al. The obligate respiratory supercomplex from Actinobacteria. Biochim. Biophys. Acta Bioenerg. 1857, 1705–1714 (2016).

    Article  CAS  Google Scholar 

  89. Buschmann, S. et al. The structure of cbb3 cytochrome oxidase provides insights into proton pumping. Science 329, 327–330 (2010).

    Article  PubMed  CAS  Google Scholar 

  90. Lyons, J. A. et al. Structural insights into electron transfer in Caa3-type cytochrome oxidases. Nature 487, 514–518 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Abramson, J. et al. The structure of the ubiquinol oxidase from Escherichia coli and its ubiquinone binding site. Nat. Struct. Biol. 7, 910–917 (2000).

    Article  PubMed  CAS  Google Scholar 

  92. Xu, J. et al. Structure of the cytochrome aa3-600 heme-copper menaquinol oxidase bound to inhibitor HQNO shows TM0 is part of the quinol binding site. Proc. Natl Acad. Sci. USA 117, 872–876 (2020).

    Article  PubMed  CAS  Google Scholar 

  93. Wikström, M., Sharma, V., Kaila, V. R. I., Hosler, J. P. & Hummer, G. New perspectives on proton pumping in cellular respiration. Chem. Rev. 115, 2196–2221 (2015).

    Article  PubMed  Google Scholar 

  94. Wikström, M. K. F. Proton pump coupled to cytochrome c oxidase in mitochondria. Nature 266, 271–273 (1977). The discovery of cytochrome oxidase as a proton pump.

    Article  PubMed  Google Scholar 

  95. Pereira, M. M., Santana, M. & Teixeira, M. A novel scenario for the evolution of haem-copper oxygen reductases. Biochim. Biophys. Acta Bioenerg. 1505, 185–208 (2001).

    Article  CAS  Google Scholar 

  96. Chang, H. Y., Hemp, J., Chen, Y., Fee, J. A. & Gennis, R. B. The cytochrome ba3 oxygen reductase from Thermus thermophilus uses a single input channel for proton delivery to the active site and for proton pumping. Proc. Natl Acad. Sci. USA 106, 16169–16173 (2009).

    Article  PubMed  CAS  Google Scholar 

  97. Rauhamäki, V., Bloch, D. A. & Wikström, M. Mechanistic stoichiometry of proton translocation by cytochrome cbb3. Proc. Natl Acad. Sci. USA 109, 7286–7291 (2012).

    Article  PubMed  Google Scholar 

  98. Hendriks, J. H., Jasaitis, A., Saraste, M. & Verkhovsky, M. I. Proton and electron pathways in the bacterial nitric oxide reductase. Biochemistry 41, 2331–2340 (2002).

    Article  PubMed  CAS  Google Scholar 

  99. Blomberg, M. R. A. & Ädelroth, P. Mechanisms for enzymatic reduction of nitric oxide to nitrous oxide - A comparison between nitric oxide reductase and cytochrome c oxidase. Biochim. Biophys. Acta Bioenerg. 1859, 1223–1234 (2018).

    Article  PubMed  CAS  Google Scholar 

  100. Gonska, N. et al. Characterization of the quinol-dependent nitric oxide reductase from the pathogen Neisseria meningitidis, an electrogenic enzyme. Sci. Rep. 8, 3637 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wikström, M., Krab, K. & Sharma, V. Oxygen activation and energy conservation by cytochrome c oxidase. Chem. Rev. 118, 2469–2490 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Belevich, I., Verkhovsky, M. I. & Wikström, M. Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase. Nature 440, 829–832 (2006).

    Article  PubMed  CAS  Google Scholar 

  103. Wikström, M., Verkhovsky, M. I. & Hummer, G. Water-gated mechanism of proton translocation by cytochrome c oxidase. Biochim. Biophys. Acta Bioenerg. 1604, 61–65 (2003).

    Article  Google Scholar 

  104. Supekar, S. & Kaila, V. R. I. Dewetting transitions coupled to K-channel activation in cytochrome c oxidase. Chem. Sci. 9, 6703–6710 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Saura, P., Frey, D. M., Gamiz-Hernandez, A. P. & Kaila, V. R. I. Electric field modulated redox-driven protonation and hydration energetics in energy converting enzymes. Chem. Comm. 55, 6078–6081 (2019).

    Article  PubMed  CAS  Google Scholar 

  106. Kaila, V. R. I., Verkhovsky, M. I., Hummer, G. & Wikström, M. Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase. Proc. Natl Acad. Sci. USA 105, 6255–6259 (2008).

    Article  PubMed  CAS  Google Scholar 

  107. Rauhamäki, V., Bloch, D. A., Verkhovsky, M. I. & Wikström, M. Active site of cytochrome cbb3. J. Biol. Chem. 284, 11301–11308 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Huang, Y., Reimann, J., Lepp, H., Drici, N. & Ädelroth, P. Vectorial proton transfer coupled to reduction of O2 and NO by a heme-copper oxidase. Proc. Natl Acad. Sci. USA 105, 20257–20262 (2008).

    Article  PubMed  CAS  Google Scholar 

  109. Puustinen, A. & Wikström, M. The heme groups of cytochrome o from Escherichia coli. Proc. Natl Acad. Sci. USA 88, 6122–6126 (1991).

    Article  PubMed  CAS  Google Scholar 

  110. Safarian, S. et al. Active site rearrangement and structural divergence in prokaryotic respiratory oxidases. Science 366, 100–104 (2019).

    Article  PubMed  CAS  Google Scholar 

  111. Safarian, S. et al. Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science 352, 583–586 (2016). The molecular structure of the bacterial bd oxidase.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Cunningham, L., M. Pitt, M. & Williams, H. D. The cioAB genes from Pseudomonas aeruginosa code for a novel cyanide-insensitive terminal oxidase related to the cytochrome bd quinol oxidases. Mol. Microbiol. 24, 579–591 (1997).

    Article  PubMed  CAS  Google Scholar 

  113. Schägger, H. Respiratory chain supercomplexes of mitochondria and bacteria. Biochim. Biophys. Acta 1555, 154–159 (2002).

    Article  PubMed  Google Scholar 

  114. Letts, J. A., Fiedorczuk, K., Degliesposti, G., Skehel, M. & Sazanov, L. A. Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk. Mol. Cell 75, 1131–1146.e6 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Davies, K. M., Blum, T. B. & Kühlbrandt, W. Conserved in situ arrangement of complex I and III(2) in mitochondrial respiratory chain supercomplexes of mammals, yeast, and plants. Proc. Natl Acad. Sci. USA 115, 3024–3029 (2018).

    Article  PubMed  CAS  Google Scholar 

  116. Stuchebrukhov, A., Schäfer, J., Berg, J. & Brzezinski, P. Kinetic advantage of forming respiratory supercomplexes. Biochim. Biophys. Acta Bioenerg. 1861, 148193 (2020).

    Article  PubMed  CAS  Google Scholar 

  117. Bianchi, C., Genova, M. L., Parenti Castelli, G. & Lenaz, G. The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J. Biol. Chem. 279, 36562–36569 (2004).

    Article  PubMed  CAS  Google Scholar 

  118. Fedor, J. G. & Hirst, J. Mitochondrial supercomplexes do not enhance catalysis by quinone channeling. Cell Metab. 28, 525–531.e4 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Blaza, J. N., Serreli, R., Jones, A. J. Y., Mohammed, K. & Hirst, J. Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes. Proc. Natl Acad. Sci. USA 111, 15735–15740 (2014).

    Article  PubMed  CAS  Google Scholar 

  120. Efremov, R. G. & Sazanov, L. A. Structure of the membrane domain of respiratory complex I. Nature 476, 414–420 (2011).

    Article  PubMed  CAS  Google Scholar 

  121. Heikal, A. et al. Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation. Mol. Microbiol. 91, 950–964 (2014).

    Article  PubMed  CAS  Google Scholar 

  122. Sousa, F. M. et al. The key role of glutamate 172 in the mechanism of type II NADH:quinone oxidoreductase of Staphylococcus aureus. Biochim. Biophys. Acta Bioenerg. 1858, 823–832 (2017).

    Article  PubMed  CAS  Google Scholar 

  123. Kleinschroth, T. et al. X-ray structure of the dimeric cytochrome bc(1) complex from the soil bacterium Paracoccus denitrificans at 2.7-Å resolution. Biochim. Biophys. Acta Bionenerg. 1807, 1606–1615 (2011).

    Article  CAS  Google Scholar 

  124. Koepke, J. et al. High resolution crystal structure of Paracoccus denitrificans cytochrome c oxidase: New insights into the active site and the proton transfer pathways. Biochim. Biophys. Acta Bioenerg. 1787, 635–645 (2009).

    Article  CAS  Google Scholar 

  125. Tiefenbrunn, T. et al. High resolution structure of the ba3 cytochrome c oxidase from Thermus thermophilusin a lipidic environment. PLoS ONE 6, e22348 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Thesseling, A. et al. Homologous bd oxidases share the same architecture but differ in mechanism. Nat. Commun. 10, 5138–5138 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

V.R.I.K. acknowledges insightful discussion with P. Brzezinski, as well as all members of the Kaila laboratory. This work was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation program/grant agreement 715311, and the Knut and Alice Wallenberg Foundation (V.R.I.K.). M.W. acknowledges a grant from the Magnus Ehrnrooth Foundation. This work was also supported by the Swedish National Infrastructure for Computing (SNIC 2020/1-38) at PDC Center for High Performance Computing, partially funded by the Swedish Research Council through grant agreement no. 2016-07213.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Ville R. I. Kaila.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Microbiology thanks Robert Gennis, John Rubinstein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Zwitterionic lipids

Lipid molecules that carry both negative and positive electric point charges.

Desolvation (Born) free energy

The electrostatic component of Gibbs free energy arising from ion solvation.

Grotthuss-type hopping process

An excess proton that diffuses within a hydrogen-bonded network of residues via the concerted formation and breaking of covalent bonds between donor and acceptor pairs, followed by reorientation of the hydrogen-bonded network. Named after C. J. D. T. von Grotthuss, who proposed the mechanism in 1806.

Rieske Fe–S protein

The Rieske Fe-S protein is the 2Fe–2S centre of complex III and is named after its discoverer, John S. Rieske.

Mitchellian redox-loop mechanism

The ‘redox loop’ is the original proton translocation principle in Peter Mitchell’s chemiosmotic theory, which involves direct electron transfer from the P-side to the N-side and coupled proton release and uptake reactions at respective sides of the membrane.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaila, V.R.I., Wikström, M. Architecture of bacterial respiratory chains. Nat Rev Microbiol 19, 319–330 (2021). https://doi.org/10.1038/s41579-020-00486-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-020-00486-4

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing