Skip to main content
SpringerLink
Log in

Opposite Rotation Directions in the Synthesis and Hydrolysis of ATP by the ATP Synthase: Hints from a Subunit Asymmetry

  • Topical Review
  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

The ATP synthase can be imagined as a reversible H+-translocating channel embedded in the membrane, FO portion, coupled to a protruding catalytic portion, F1. Under physiological conditions the F1FO complex synthesizes ATP by exploiting the transmembrane electrochemical gradient of protons and their downhill movement. Alternatively, under other patho-physiological conditions it exploits ATP hydrolysis to energize the membrane by uphill pumping protons. The reversibility of the mechanism is guaranteed by the structural coupling between the hydrophilic F1 and the hydrophobic FO. Which of the two opposite processes wins in the energy-transducing membrane complex depends on the thermodynamic balance between the protonmotive force (Δp) and the phosphorylation potential of ATP (ΔG P). Accordingly, while Δp prevalence drives ATP synthesis by translocating protons from the membrane P-side to the N-side and generating anticlockwise torque rotation (viewed from the matrix), ΔG P drives ATP hydrolysis by chemomechanical coupling of FO to F1 with clockwise torque. The direction of rotation is the same in all the ATP synthases, due to the conserved steric arrangement of the chiral a subunit of FO. The ability of this coupled bi-functional complex to produce opposite rotations in ATP synthesis and hydrolysis is explained on the basis of the a subunit asymmetry.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Angevine CM, Fillingame RH (2003) Aqueous access channels in subunit a of rotary ATP synthase. J Biol Chem 278:6066–6074

    Article  CAS  PubMed  Google Scholar 

  • Baker LA, Watt IA, Runswick MJ, Walker JE, Rubinstein JL (2012) Arrangement of subunits in intact mammalian mitochondrial ATP synthase determined by cryo-AM. Proc Natl Acad Sci USA 109:11675–11680

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bonora M, Wieckowski MR, Chinopoulos C, Kepp O, Kroemer G, Galluzzi L, Pinton P (2014) Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene. doi:10.1038/onc.2014.96

    PubMed  Google Scholar 

  • Boyer PD (1988) Bioenergetic coupling to protonmotive force: should we be considering hydronium ion coordination and not group protonation? Trends Biochem Sci 13:5–7

    Article  CAS  PubMed  Google Scholar 

  • Boyer PD (1993) The binding change mechanism for ATP synthase-some probabilities and possibilities. Biochim Biophys Acta 1140:215–250

    Article  CAS  PubMed  Google Scholar 

  • Boyer PD (1997) The ATP synthase-a splendid molecular machine. Annu Rev Biochem 66:717–749

    Article  CAS  PubMed  Google Scholar 

  • Cabezón E, Runswick MJ, Leslie AG, Walker JE (2001) The structure of bovine IF1, the regulatory subunit of mitochondrial F-ATPase. EMBO J 20:6990–6996

    Article  PubMed Central  PubMed  Google Scholar 

  • Capaldi RA, Aggeler R (2002) Mechanism of the F0F1-type ATP synthase, a biological rotary motor. Trends Biochem Sci 27:154–160

    Article  CAS  PubMed  Google Scholar 

  • Dabbeni-Sala F, Rai AK, Lippe G (2012) F0F1 ATP synthase: a fascinating challenge for proteomics. In Tsz Kwong Man & Flores RJ (Eds), Proteomics - human diseases and protein functions, (pp 161–168), InTech, Rijeka, Croatia, www.intechopen.com

  • Daum B, Walter A, Horst A, Osiewacz HD, Kühlbrandt W (2013) Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria. Proc Natl Acad Sci USA 110:15301–15306

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Deckers-Hebenstreit G, Alterdorf K (1996) The FOF1-type ATP synthases in bacteria: structure and function of the FO complex. Annu Rev Microbiol 50:791–824

    Article  Google Scholar 

  • Devenish RJ, Prescott M, Rodgers AJ (2008) The structure and function of mitochondrial F1F0-ATP synthases. Int Rev Cell Mol Biol 267:1–58

    Article  CAS  PubMed  Google Scholar 

  • Dimroth P, von Ballmoos C, Meier T (2006) Catalytic and mechanical cycles in F-ATP synthases. Fourth in the cycles review series. EMBO Rep 7:276–282

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Elston T, Wang H, Oster G (1998) Energy transduction in ATP synthase. Nature 391:510–513

    Article  CAS  PubMed  Google Scholar 

  • Ferguson SJ (2010) ATP synthase: from sequence to ring size to the P/O ratio. Proc Natl Acad Sci 107:16755–16756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gibbons C, Montgomery MG, Leslie AG, Walker JE (2000) The structure of the central stalk in bovine F1-ATPase at 2.4 Å resolution. Nat Struct Biol 7:1055–1061

    Article  CAS  PubMed  Google Scholar 

  • Giorgio V, von Strockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci 110:5887–5992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gledhill JR, Montgomery MG, Leslie AG, Walker JE (2007) How the regulatory protein, IF1, inhibits F1-ATPase from bovine mitochondria. Proc Natl Acad Sci USA 104:15671–15676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Goodsell DS, Olson AJ (2000) Structural symmetry and protein function. Annu Rev Biophys Biomol Struct 29:105–153

    Article  CAS  PubMed  Google Scholar 

  • Grover GJ, Malm J (2009) Pharmacological profile of the selective mitochondrial F1FO ATP hydrolase inhibitor BMS-1999264 in myocardial ischemia. Cardiovasc Ther 26:287–296

    Article  Google Scholar 

  • Gujarro A, Yus M (2009) The origin of chirality in the molecules of life: a revision from awareness to the current theories and perspectives of this unsolved problem. RCS Publishing, Cambridge

    Google Scholar 

  • Habersetzer J, Larrieu I, Priault M, Salin B, Rossignol R, Brèthes D, Poumard P (2013) Human F1FO ATP synthase, mitochondrial ultrastructure and OXPHOS impairment: a (super-) complex matter? PLoS ONE 8:e75429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johnson JA, Ogbi M (2011) Targeting the F1FO ATP Synthase: modulation of the body’s powerhouse and its implications for human disease. Curr Med Chem 18:4684–45714

    Article  CAS  PubMed  Google Scholar 

  • Jonckheere AI, Smeitink JAM, Rodenburg RJT (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35:211–225

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Junge W, Lill H, Engelbrecht S (1997) ATP synthase: an electrochemical transducer with rotatory mechanics. Trends Biochem Sci 22:420–423

    Article  CAS  PubMed  Google Scholar 

  • Junge W, Sielaff H, Engelbrecht S (2009) Torque generation and elastic power transmission in the rotary FoF1-ATPase. Nature 459:364–370

    Article  CAS  PubMed  Google Scholar 

  • Mitome N, Ono S, Sato H, Suzuki T, Sone N, Yoshida M (2010) Essential arginine residue of the Fo-a subunit in FoF1-ATP synthase has a role to prevent the proton shortcut without c-ring rotation in the Fo proton channel. Biochem J 430:171–177

    Article  CAS  PubMed  Google Scholar 

  • Nesci S, Ventrella V, Trombetti F, Pirini M, Pagliarani A (2013) Mussel and mammalian ATP synthase share the same bioenergetic cost of ATP. J Bioenerg Biomembr 45:289–300

    Article  CAS  PubMed  Google Scholar 

  • Nesci S, Ventrella V, Trombetti F, Pirini M, Pagliarani A (2014) Thiol oxidation of mitochondrial FO-c subunits: a way to switch off antimicrobial drug targets of the mitochondrial ATP synthase. Med Hypot 83:160–165

    Article  CAS  Google Scholar 

  • Nicholls DG, Ferguson SJ (2013) Bioenergetics 4. Accademic Press, Amsterdam

    Google Scholar 

  • Pogoryelov D, Yildiz O, Faraldo-Gómez JD, Meier T (2009) High-resolution structure of the rotor ring of a proton-dependent ATP synthase. Nat Struct Mol Biol 16:1068–1073

    Article  CAS  PubMed  Google Scholar 

  • Pogoryelov D, Krah A, Langer JD, Yildiz Ö, Faraldo-Gómez JD, Meier T (2010) Microscopic rotary mechanism of ion translocation in the Fo complex of ATP synthases. Nat Chem Biol 6:891–899

    Article  CAS  PubMed  Google Scholar 

  • Sakthivel S (2012) ATP-ase as a potential drug target for cancer, tumor growth and cellular functions. Int J Hum Genet 12:151–156

    CAS  Google Scholar 

  • Seelert H, Dencher NA (2001) ATP synthase superassemblies in animals and plants: two or more are better. Biochim Biophys Acta 1807:1185–1197

    Article  Google Scholar 

  • Sielaff H, Bőrsch M (2013) Twisting and subunit rotation in single FOF1-ATP synthase. Phil Trans R Soc B 368:20120024. doi:10.1098/rstb.2012.0024

    Article  PubMed Central  PubMed  Google Scholar 

  • Silverstein TP (2014) An exploration of how the thermodynamic efficiency of bioenergetic membrane systems varies with c-subunit stoichiometry of F1FO ATP synthases. J Bioenerg Biomembr 46:229–241

    Article  CAS  PubMed  Google Scholar 

  • Stock D, Leslie AG, Walker JE (1999) Molecular architecture of the rotary motor in ATP synthase. Science 286:1700–1705

    Article  CAS  PubMed  Google Scholar 

  • Strauss M, Hofhaus G, Schröder RR, Kühlbrandt W (2008) Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J 27:1154–1160

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sun SX, Wang H, Oster G (2004) Asymmetry in the F1-ATPase and its implications for the rotational cycle. Biophys J 86:1373–1384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Symersky J, Pagadala V, Osowski D, Krah A, Meier T, Faraldo-Gómez JD, Mueller DM (2012) Structure of the c(10) ring of the yeast mitochondrial ATP synthase in the open conformation. Nat Struct Mol Biol 19:485–491

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Uchihashi T, Iino R, Ando T, Noji H (2011) High-speed atomic force microscopi reveals rotary catalysis of rotorless F1-ATPase. Science 333:755–758

    Article  CAS  PubMed  Google Scholar 

  • Vik SB, Ishmukhametov RR (2005) Structure and function of subunit a of the ATP synthase of Escherichia coli. J Bioenerg Biomembr 37:445–449

    Article  CAS  PubMed  Google Scholar 

  • von Ballmoos C, Cook GM, Dimroth P (2008) Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys 37:43–64

    Article  Google Scholar 

  • von Ballmoos C, Wiedenmann A, Dimroth P (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annu Rev Biochem 78:649–672

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Walker JE, Dickson VK (2006) The peripheral stalk of the mitochondrial ATP synthase. Biochim Biophys Acta 1757:286–296

    Article  CAS  PubMed  Google Scholar 

  • Watanabe R, Noji H (2013) Chemomechanical coupling mechanism of F1-ATPase: catalysis and torque generation. FEBS Lett 587:1030–1035

    Article  CAS  PubMed  Google Scholar 

  • Watt IN, Montgomery MG, Runswick MJ, Leslie AG, Walker JE (2010) Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci 107:16823–16827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy

    Salvatore Nesci, Fabiana Trombetti, Vittoria Ventrella & Alessandra Pagliarani

Authors
  1. Salvatore Nesci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabiana Trombetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vittoria Ventrella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessandra Pagliarani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandra Pagliarani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nesci, S., Trombetti, F., Ventrella, V. et al. Opposite Rotation Directions in the Synthesis and Hydrolysis of ATP by the ATP Synthase: Hints from a Subunit Asymmetry. J Membrane Biol 248, 163–169 (2015). https://doi.org/10.1007/s00232-014-9760-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-014-9760-y

Keywords

Search

Navigation