Coenzyme Q and respiratory supercomplexes: physiological and pathological implications

  • Giorgio Lenaz
  • Gaia Tioli
  • Anna Ida Falasca
  • Maria Luisa Genova
Current topics in Biology


It was discovered over 60 years ago that the mitochondrial respiratory chain is constituted of a series of protein complexes imbedded in the inner mitochondrial membrane. Experimental evidence has more recently ascertained that the major respiratory complexes involved in energy conservation are assembled as supramolecular units (supercomplexes, SCs) in stoichiometric ratios. The functional role of SCs is less well defined, and still open to discussion. Several lines of evidence favour the concept that electron transfer from Complex I to Complex III operates by channelling of electrons through Coenzyme Q molecules bound to the SC I1III2IV n , in contrast with the previously accepted hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. On the contrary, electron transfer from Complex III to Complex IV seems to operate, at least in mammals, by random diffusion of cytochrome c molecules between the respiratory complexes even if assembled in SCs. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I, that might be important in the regulation of signal transduction from mitochondria. This review discusses physiological and pathological implications of the supercomplex assembly of the respiratory chain.


Mitochondria Respiratory chain Supercomplexes Channelling Reactive oxygen species 


Compliance with ethical standards

Conflict of interest

The author declare that no conflict of interest exists.


  1. Acin-Perez R, Enriquez JA (2014) The function of the respiratory supercomplexes: the plasticity model. Biochim Biophys Acta 1837:444–450CrossRefGoogle Scholar
  2. Acín-Pérez R, Fernández-Silva P, Peleato ML, Pérez-Martos A, Enriquez JA (2008) Respiratory active mitochondrial supercomplexes. Mol Cell 32:529–539CrossRefGoogle Scholar
  3. Althoff T, Mills DJ, Popot JL, Kühlbrandt W (2011) Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1. EMBO J 30:4652–4664CrossRefGoogle Scholar
  4. Andreyev AY, Kushnareva YE, Murphy AN, Starkov AA (2015) Mitochondrial ROS metabolism: 10 years later. Biochem (Mosc) 80:517–531CrossRefGoogle Scholar
  5. Aon MA, Cortassa S, O’Rourke B (2010) Redox-optimized ROS balance: a unifying hypothesis. Biochim Biophys Acta 1797:865–877CrossRefGoogle Scholar
  6. Baracca A, Chiaradonna F, Sgarbi G, Solaini G, Alberghina L, Lenaz G (2010) Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells. Biochim Biophys Acta 1797:314–323CrossRefGoogle Scholar
  7. Benard G, Faustin B, Galinier A, Rocher C, Bellance N, Smolkova K, Casteilla L, Rossignol R, Letellier T (2008) Functional dynamic compartmentalization of respiratory chain intermediate substrates: implications for the control of energy production and mitochondrial diseases. Int J Biochem Cell Biol 40:1543–1554CrossRefGoogle Scholar
  8. Bianchi C, Fato R, Genova ML, Parenti Castelli G, Lenaz G (2003) Structural and functional organization of Complex I in the mitochondrial respiratory chain. BioFactors 18:3–9CrossRefGoogle Scholar
  9. Bianchi C, Genova ML, Parenti Castelli G, Lenaz G (2004) The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J Biol Chem 279:36562–36569CrossRefGoogle Scholar
  10. Blaza JN, Serreli R, Jones AJ, Mohammed K, Hirst J (2014) Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes. Proc Natl Acad Sci USA 111:15735–15740CrossRefGoogle Scholar
  11. Chance B, Williams GR (1955) A method for the localization of sites for oxidative phosphorylation. Nature 176:250–254CrossRefGoogle Scholar
  12. Chen S, He Q, Greenberg ML (2008) Loss of tafazzin in yeast leads to increased oxidative stress during respiratory growth. Mol Microbiol 68:1061–1072CrossRefGoogle Scholar
  13. Cortassa S, O’Rourke B, Aon MA (2014) Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS. Biochim Biophys Acta 1837:287–295CrossRefGoogle Scholar
  14. Covian R, Zwicker K, Rotsaert FA, Trumpower BL (2007) Asymmetric and redox-specific binding of quinone and quinol at center N of the dimeric yeast cytochrome bc1 complex. Consequences for semiquinone stabilization. J Biol Chem 282:24198–24208CrossRefGoogle Scholar
  15. Crane FL, Hatefi Y, Lester RL, Widmer C (1957) Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 25:220–221CrossRefGoogle Scholar
  16. Crane FL, Widmer C, Lester RL, Hatefi Y (1959) Studies on the electron transport system. XV. Coenzyme Q (Q275) and the succinoxidase activity of the electron transport particle. Biochim Biophys Acta 31:476–489CrossRefGoogle Scholar
  17. Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F (2007) Proteome alterations in rat mitochondria caused by aging. Ann N Y Acad Sci 1100:291–298CrossRefGoogle Scholar
  18. Diaz F, Enríquez JA, Moraes CT (2012) Cells lacking Rieske iron-sulfur protein have a reactive oxygen species-associated decrease in respiratory complexes I and IV. Mol Cell Biol 32:415–429CrossRefGoogle Scholar
  19. Dudkina NV, Kudryashev M, Stahlberg H, Boekema EJ (2011) Interaction of complexes I, III, and IV within the bovine respirasome by single particle cryoelectron tomography. Proc Natl Acad Sci USA 108:15196–15200CrossRefGoogle Scholar
  20. Enríquez JA (2016) Supramolecular organization of respiratory complexes. Annu Rev Physiol 78:533–561CrossRefGoogle Scholar
  21. Estornell E, Fato R, Castelluccio C, Cavazzoni M, Parenti Castelli G, Lenaz G (1992) Saturation kinetics of coenzyme Q in NADH and succinate oxidation in beef heart mitochondria. FEBS Lett 311:107–109CrossRefGoogle Scholar
  22. Fato R, Estornell E, Di Bernardo S, Pallotti F, Parenti Castelli G, Lenaz G (1996) Steady-state kinetics of the reduction of coenzyme Q analogs by complex I (NADH:ubiquinone oxidoreductase) in bovine heart mitochondria and submitochondrial particles. Biochemistry 35:2705–2716CrossRefGoogle Scholar
  23. Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA (2016) Atomic structure of the entire mammalian mitochondrial complex I. Nature 538:406–410CrossRefGoogle Scholar
  24. Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA, Xia D (2003) Structural basis for the quinone reduction in the bc1 complex: a comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site. Biochemistry 42:9067–9080CrossRefGoogle Scholar
  25. Genova ML, Lenaz G (2010) Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject. Antioxid Redox Signal 12:961–1008CrossRefGoogle Scholar
  26. Genova ML, Lenaz G (2013) A critical appraisal of the role of respiratory supercomplexes in mitochondria. Biol Chem 394:631–639CrossRefGoogle Scholar
  27. Genova ML, Lenaz G (2014) Functional role of mitochondrial respiratory supercomplexes. Biochim Biophys Acta 1837:427–443CrossRefGoogle Scholar
  28. Genova ML, Lenaz G (2015) The interplay between respiratory supercomplexes and ROS in aging. Antioxid Redox Signal 23:208–238CrossRefGoogle Scholar
  29. Genova ML, Baracca A, Biondi A, Casalena G, Faccioli M, Falasca AI, Formiggini G, Sgarbi G, Solaini G, Lenaz G (2008) Is supercomplex organization of the respiratory chain required for optimal electron transfer activity? Biochim Biophys Acta 1777:740–746CrossRefGoogle Scholar
  30. Gonzalvez F, D’Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauné-Pelloquin L, Vial G, Taleux N, Slomianny C, Wanders RJ, Houtkooper RH, Bellenguer P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX (2013) Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation. Biochim Biophys Acta 1832:1194–1206CrossRefGoogle Scholar
  31. Green DE, Tzagoloff A (1966) The mitochondrial electron transfer chain. Arch Biochem Biophys 116:293–304CrossRefGoogle Scholar
  32. Grivennikova VG, Roth R, Zakharova NV, Hägerhäll C, Vinogradov AD (2003) The mitochondrial and prokaryotic proton-translocating NADH: ubiquinone oxidoreductases: similarities and dissimilarities of the quinone-junction sites. Biochim Biophys Acta 1607:79–90CrossRefGoogle Scholar
  33. Guarás A, Perales-Clemente E, Calvo E, Acín-Pérez R, Loureiro-Lopez M, Pujol C, Martínez-Carrascoso I, Nuñez E, García-Marqués F, Rodríguez-Hernández MA, Cortés A, Diaz F, Pérez-Martos A, Moraes CT, Fernández-Silva P, Trifunovic A, Navas P, Vazquez J, Enríquez JA (2016) The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency. Cell Rep 15:197–209CrossRefGoogle Scholar
  34. Gutman M (1985) Kinetic analysis of electron flux through the quinones in the mitochondrial system. In: Lenaz G (ed) Coenzyme Q. Wiley, Chichester, pp 215–234Google Scholar
  35. Gutman M, Silman N (1972) Mutual inhibition between NADH oxidase and succinoxidase activities in respiring submitochondrial particles. FEBS Lett 26:207–210CrossRefGoogle Scholar
  36. Gutman M, Kearney EB, Singer TP (1971) Control of succinate dehydrogenase in mitochondria. Biochemistry 10:4763–4770CrossRefGoogle Scholar
  37. Hackenbrock CR, Chazotte B, Gupte SS (1986) The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport. J Bioenerg Biomembr 18:331–368CrossRefGoogle Scholar
  38. Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962a) Studies on the electron transfer system. XLII. Reconstitution of the electron transfer system. J Biol Chem 237:2661–2669Google Scholar
  39. Hatefi Y, Haavik AG, Griffiths DE (1962b) Studies on the electron transfer system. XL. Preparation and properties of mitochondrial DPNH-coenzyme Q reductase. J Biol Chem 237:1676–1680Google Scholar
  40. Heron C, Ragan CI, Trumpower BL (1978) The interaction between mitochondrial NADH-ubiquinone oxidoreductase and ubiquinol-cytochrome c oxidoreductase. Restoration of ubiquinone-pool behaviour. Biochem J 174:791–800Google Scholar
  41. Hochman J, Ferguson-Miller S, Schindler M (1985) Mobility in the mitochondrial electron transport chain. Biochemistry 24:2509–2516CrossRefGoogle Scholar
  42. Jezek P, Hlavatá L (2005) Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 37:2478–2503CrossRefGoogle Scholar
  43. Jones AJ, Blaza JN, Bridges HR, May B, Moore AL, Hirst J (2016) A self-assembled respiratory chain that catalyzes NADH oxidation by ubiquinone-10 cycling between complex I and the alternative oxidase. Angew Chem Int Ed Engl 55:728–731CrossRefGoogle Scholar
  44. Jørgensen BM, Rasmussen HN, Rasmussen UF (1985) Ubiquinone reduction pattern in pigeon heart mitochondria. Identification of three distinct ubiquinone pools. Biochem J 229:621–629CrossRefGoogle Scholar
  45. Kaambre T, Chekulayev V, Shevchuk I, Karu-Varikmaa M, Timohhina N, Tepp K, Bogovskaja J, Kütner R, Valvere V, Saks V (2012) Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. J Bioenerg Biomembr 44:539–558CrossRefGoogle Scholar
  46. Kaambre T, Chekulayev V, Shevchuk I, Tepp K, Timohhina N, Varikmaa M, Bagur R, Klepinin A, Anmann T, Koit A, Kaldma A, Guzun R, Valvere V, Saks V (2013) Metabolic control analysis of respiration in human cancer tissue. Front Physiol 4:151. CrossRefGoogle Scholar
  47. Kennedy EP, Lehninger AL (1949) Oxidation of fatty acids and tricarboxylic acid intermediates by isolated rat liver mitochondria. J Biol Chem 179:957–972Google Scholar
  48. Kholodenko BN, Westerhoff HV (1993) Metabolic channelling and control of the flux. FEBS Lett 320:71–74CrossRefGoogle Scholar
  49. Kröger A, Klingenberg M (1973a) The kinetics of the redox reactions of ubiquinone related to the electron-transport activity in the respiratory chain. Eur J Biochem 34:358–368CrossRefGoogle Scholar
  50. Kröger A, Klingenberg M (1973b) Further evidence for the pool function of ubiquinone as derived from the inhibition of the electron transport by antimycin. Eur J Biochem 39:313–323CrossRefGoogle Scholar
  51. Lapuente-Brun E, Moreno-Loshuertos R, Acín-Pérez R, Latorre-Pellicer A, Colás C, Balsa E, Perales-Clemente E, Quirós PM, Calvo E, Rodríguez-Hernández MA, Navas P, Cruz R, Carracedo Á, López-Otín C, Pérez-Martos A, Fernández-Silva P, Fernández-Vizarra E, Enríquez JA (2013) Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 340:1567–1570CrossRefGoogle Scholar
  52. Lenaz G (2001) The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 52:159–164CrossRefGoogle Scholar
  53. Lenaz G (2012) Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv Exp Med Biol 942:93–136CrossRefGoogle Scholar
  54. Lenaz G, Fato R (1986) Is ubiquinone diffusion rate-limiting for electron transfer? J Bioenerg Biomembr 18:369–401CrossRefGoogle Scholar
  55. Lenaz G, Genova ML (2007) Kinetics of integrated electron transfer in the mitochondrial respiratory chain: random collisions vs. solid state electron channeling. Am J Physiol Cell Physiol 292:C1221–C1239CrossRefGoogle Scholar
  56. Lenaz G, Baracca A, Barbero G, Bergamini C, Dalmonte ME, Del Sole M, Faccioli M, Falasca A, Fato R, Genova ML, Sgarbi G, Solaini G (2010) Mitochondrial respiratory chain super-complex I–III in physiology and pathology. Biochim Biophys Acta 1797:633–640CrossRefGoogle Scholar
  57. Lenaz G, Tioli G, Falasca AI, Genova ML (2016) Complex I function in mitochondrial supercomplexes. Biochim Biophys Acta 1857:991–1000CrossRefGoogle Scholar
  58. Letts JA, Sazanov LA (2017) Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 24:800–808CrossRefGoogle Scholar
  59. Letts JA, Fiedorczuk K, Sazanov LA (2016) The architecture of respiratory supercomplexes. Nature 537:644–648CrossRefGoogle Scholar
  60. Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML (2013) Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal 19:1469–1480CrossRefGoogle Scholar
  61. McKenzie M, Lazarou M, Thorburn DR, Ryan MT (2006) Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol 361:462–469CrossRefGoogle Scholar
  62. Milenkovic D, Blaza JN, Larsson NG, Hirst J (2017) The enigma of the respiratory chain supercomplex. Cell Metab 25:765–776CrossRefGoogle Scholar
  63. Mitchell P (1975) The protonmotive Q cycle: a general formulation. FEBS Lett 59:137–139CrossRefGoogle Scholar
  64. Morton RA (1958) Ubiquinone. Nature 182:1764–1767CrossRefGoogle Scholar
  65. Ovádi J (1991) Physiological significance of metabolic channelling. J Theor Biol 152:1–22CrossRefGoogle Scholar
  66. Ozawa T, Nishikimi M, Suzuki H, Tanaka M, Shimomura Y (1987) Structure and assembly of mitochondrial electron-transfer complexes. In: Ozawa T, Papa S (eds) Bioenergetics: structure and function of energy-transducing systems. Japan Science Society Press, Tokyo, pp 101–119Google Scholar
  67. Panov A, Dikalov S, Shalbuyeva N, Hemendinger R, Greenamyre JT, Rosenfeld J (2007) Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol 292:C708–C718CrossRefGoogle Scholar
  68. Piccoli C, Scrima R, Boffoli D, Capitanio N (2006) Control by cytochrome c oxidase of the cellular oxidative phosphorylation system depends on the mitochondrial energy state. Biochem J 396:573–583CrossRefGoogle Scholar
  69. Quarato G, Piccoli C, Scrima R, Capitanio N (2011) Variation of flux control coefficient of cytochrome c oxidase and of the other respiratory chain complexes at different values of protonmotive force occurs by a threshold mechanism. Biochim Biophys Acta 1807:1114–1124CrossRefGoogle Scholar
  70. Ragan CI, Heron C (1978) The interaction between mitochondrial NADH-ubiquinone oxidoreductase and ubiquinol-cytochrome c oxidoreductase. Evidence for stoicheiometric association. Biochem J 174:783–790Google Scholar
  71. Ragan CI, Cottingham IR (1985) The kinetics of quinone pools in electron transport. Biochim Biophys Acta 811:13–31CrossRefGoogle Scholar
  72. Redfearn ER, Pumphrey AM (1960) The kinetics of ubiquinone reactions in heart-muscle preparations. Biochem J 76:64–71CrossRefGoogle Scholar
  73. Sarewicz M, Osyczka A (2015) Electronic connection between the quinone and cytochrome C redox pools and its role in regulation of mitochondrial electron transport and redox signaling. Physiol Rev 95:219–243CrossRefGoogle Scholar
  74. Schäfer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J (2006) Architecture of active mammalian respiratory chain supercomplexes. J Biol Chem 281:15370–15375CrossRefGoogle Scholar
  75. Schägger H, Pfeiffer K (2000) Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 19:1777–1783CrossRefGoogle Scholar
  76. Schägger H, Pfeiffer K (2001) The ratio of oxidative phosphorylation complexes I–V in bovine heart mitochondria and the composition of respiratory chain supercomplexes. J Biol Chem 276:37861–37867Google Scholar
  77. Schneider H, Lemasters JJ, Hackenbrock CR (1982) Lateral diffusion of ubiquinone during electron transfer in phospholipid- and ubiquinone-enriched mitochondrial membranes. J Biol Chem 257:10789–10793Google Scholar
  78. Singer SJ, Nicolson GL (1976) The fluid mosaic model of the structure of cell membranes. Science 175:720–731CrossRefGoogle Scholar
  79. Sousa JS, Mills DJ, Vonck J, Kühlbrandt W (2016) Functional asymmetry and electron flow in the bovine respirasome. eLife 5:e21290CrossRefGoogle Scholar
  80. Stoner CD (1984) Steady-state kinetics of the overall oxidative phosphorylation reaction in heart mitochondria. Determination of the coupling relationships between the respiratory reactions and miscellaneous observations concerning rate-limiting steps. J Bioenerg Biomembr 16:115–141CrossRefGoogle Scholar
  81. Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121:1043–1057CrossRefGoogle Scholar
  82. Szarkowska L (1966) The restoration of DPNH oxidase activity by coenzyme Q (ubiquinone). Arch Biochem Biophys 113:519–525CrossRefGoogle Scholar
  83. Wittig I, Schägger H (2005) Advantages and limitations of clear-native PAGE. Proteomics 5:4338–4346CrossRefGoogle Scholar
  84. Wu M, Gu J, Guo R, Huang Y, Yang M (2016) Structure of mammalian respiratory supercomplex I1III2IV1. Cell 167:1598–1609CrossRefGoogle Scholar
  85. Yano N, Muramoto K, Shimada A, Takemura S, Baba J, Fujisawa H, Mochizuki M, Shinzawa-Itoh K, Yamashita E, Tsukihara T, Yoshikawa S (2016) The Mg2+-containing water cluster of mammalian cytochrome c oxidase collects four pumping proton equivalents in each catalytic cycle. J Biol Chem 291:23882–23894CrossRefGoogle Scholar
  86. Zhou A, Rohou A, Schep DG, Bason JV, Montgomery MG, Walker JE, Grigorieff N, Rubinstein JL (2015) Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM. eLife 4:e10180Google Scholar

Copyright information

© Accademia Nazionale dei Lincei 2018

Authors and Affiliations

  1. 1.Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum-University of BolognaBolognaItaly
  2. 2.Department of Food and DrugUniversity of ParmaParmaItaly

Personalised recommendations