Skip to main content
SpringerLink
Log in

Effects of standardized extract of Ginkgo biloba leaves EGb761 on mitochondrial functions: mechanism(s) of action and dependence on the source of mitochondria and respiratory substrate

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

In this work, the effects of standardized dry extract of Ginkgo biloba leaves, EGb761, on the respiration of rat heart and liver mitochondria were investigated. We revealed uncoupling of oxidative phosphorylation in rat heart mitochondria by EGb761 which was not observed in liver mitochondria respiring on pyruvate + malate; oxidation of succinate in heart mitochondria was inhibited by EGb761, concentration-dependently, almost completely at 1.00 mg/mL. Uncoupling effect of EGb761 was found to be due to increase in H+ and K+ permeability of inner membrane of mitochondria which is most likely to be mediated by the ATP/ADP-translocator and uncoupling proteins. EGb761 depressed State 3 respiration with pyruvate + malate (similarly in heart and liver mitochondria) and succinate (stronger than with pyruvate + malate) but not respiratory chain Complex IV; inhibition of respiration was not restored by uncoupler indicating the inhibitory action of EGb761 on the respiratory complexes preceding to Complex IV and/or on the substrate transport. Moreover, EGb761 rapidly reduced pure cytochrome c. This property of EGb761 together with the observed uncoupling of oxidative phosphorylation and reduction of H2O2 accumulation may be beneficial for the cell in the prevention of apoptosis and protection of cellular functions in pathological situations.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ANT:

Adenine nucleotide translocase

CAT:

Carboxyatractiloside

CCCP:

Carbonylcyanide p-chloromethoxyphenylhydrazone

COX:

Cytochrome c oxidase

GTP:

Guanosine 5’- triphosphate

OMM:

Outer mitochondrial membrane

MES:

4-Morpholineethanesulfonic acid

ROS:

Reactive oxygen species

UCP:

Uncoupling protein

TMPD:

N,N,N′,N′-tetramethyl-p-phenylenediamine

VDAC:

Voltage dependent anion chanel

References

  • Akhlaghi M, Bandy B (2009) Mechanisms of flavonoid protection against myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 46(3):309–317

    Article  CAS  Google Scholar 

  • Azzu V, Parker N, Brand MD (2008) High membrane potential promotes alkenal-induced mitochondrial uncoupling and influences adenine nucleotide translocase conformation. Biochem J 413(2):323–332

    Article  CAS  Google Scholar 

  • Baliutyte G, Baniene R, Trumbeckaite S, Borutaite V, Toleikis A (2010) Effects of Ginkgo biloba extract on heart and liver mitochondrial functions: mechanism(s) of action. J Bioenerg Biomembr 42(2):165–172

    Article  CAS  Google Scholar 

  • Baliutyte G, Baniene R, Gendviliene V, Martisiene I, Trumbeckaite S, Borutaite V, Toleikis A (2012) Influence of ethanol extract of Ginkgo biloba leaves on the isolated rat heart work and mitochondria functions. J Cardiovasc Pharmacol 59(5):450–457

    Article  CAS  Google Scholar 

  • Barauskaite J, Grybauskiene R, Morkuniene R, Borutaite V, Brown GC (2011) Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis. Br J Pharmacol 162(5):1136–1342

    Article  CAS  Google Scholar 

  • Borutaite V, Brown GC (2007) Mitochondrial regulation of caspase activation by cytochrome oxidase and tetramethylphenylenediamine via cytosolic cytochrome c redox state. J Biol Chem 282(43):31124–31130

    Article  CAS  Google Scholar 

  • Brierley GP, Baysal K, Jung DW (1994) Cation transport systems in mitochondria: Na+ and K+ uniports and exchangers. J Bioenerg Biomembr 26(5):519–526

    Article  CAS  Google Scholar 

  • Christen Y (2004) Ginkgo biloba and neurodegenerative disorders. Front Biosci 9:3091–3104

    Article  CAS  Google Scholar 

  • DeFaudis FV, Drieu K (2000) Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1(1):25–58

    Article  Google Scholar 

  • Diamond BJ, Bailey MR (2013) Ginkgo biloba. Indications, mechanisms, and safety. Psychiatr Clin N Am 36(1):73–83

    Article  Google Scholar 

  • Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Prado IM, Helena AF, Uyemura SA, Santos AC, Curti C (2005) The interaction of flavonoids with mitochondria: effects on energetic processes. Chem Biol Interact 152(2–3):67–78

    Article  CAS  Google Scholar 

  • Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Pestana CR, Uyemura SA, Santos AC, Curti C (2008) Antioxidant activity of flavonoids in isolated mitochondria. Phytother Res 22(9):1213–1218

    Article  CAS  Google Scholar 

  • Du G, Willet K, Mouithys-Mickalad A, Sluse-Goffart CM, Droy-Lefaix MT, Sluse FE (1999) EGb 761 protects liver mitochondria against injury induced by in vitro anoxia/reoxygenation. Free Radic Biol Med 27(5–6):596–604

    Article  CAS  Google Scholar 

  • Eckert A, Keil U, Scherping I, Hauptmann S, Müller WE (2005) Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761. Ann N Y Acad Sci 1056:474–485

    Article  Google Scholar 

  • Gledhill JR, Montgomery MG, Leslie AG, Walker JE (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci U S A 104(34):13632–13637

    Article  CAS  Google Scholar 

  • Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177(2):751–766

    CAS  Google Scholar 

  • Halestrap AP, Clarke SJ, Khaliulin I (2007) The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 1767(8):1007–1031

    Article  CAS  Google Scholar 

  • Koeppe DE, Miller RJ (1974) Kaempferol inhibitions of corn mitochondrial phosphorylation. Plant Physiol 54(3):374–378

    Article  CAS  Google Scholar 

  • Kopustinskas A, Adaskevicius R, Krusinskas A, Kopustinskiene DM, Liobikas J, Toleikis A (2006) A user-friendly PC-based data acquisition and analysis system for respirometric investigations. Comput Methods Prog Biomed 82(3):231–237

    Article  Google Scholar 

  • Lagoa R, Graziani I, Lopez-Sanchez C, Garcia-Martinez V, Gutierrez-Merino C (2011) Complex I and cytochrome c are molecular targets of flavonoids that inhibit hydrogen peroxide production by mitochondria. Biochim Biophys Acta 1807(12):1562–1572

    Article  CAS  Google Scholar 

  • Liobikas J, Kopustinskiene DM, Toleikis A (2001) What controls the outer mitochondrial membrane permeability for ADP: facts for and against the role of oncotic pressure. Biochim Biophys Acta 1505(2–3):220–225

    Article  CAS  Google Scholar 

  • Luo Y (2001) Ginkgo biloba neuroprotection: therapeutic implications in Alzheimer’s disease. J Alzheimers Dis 3(4):401–407

    CAS  Google Scholar 

  • Mahadevan S, Park Y (2008) Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. J Food Sci 73(1):4–19

    Google Scholar 

  • Mahady GB (2002) Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature. J Cardiovasc Nurs 16(4):21–32

    Article  Google Scholar 

  • Miwa S, Brand MD (2003) Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans 31(6):1300–1301

    Article  CAS  Google Scholar 

  • Nicholls DG, Ferguson SJ (1992) Bioenergetics 2. Academic, London

    Google Scholar 

  • Ortega R, García N (2009) The flavonoid quercetin induces changes in mitochondrial permeability by inhibiting adenine nucleotide translocase. J Bioenerg Biomembr 41(1):41–47

    Article  CAS  Google Scholar 

  • Panov A, Filippova S, Lyakhovich V (1980) Adenine nucleotide translocase as a site of regulation by ADP of the rat liver mitochondria permeability to H+ and K+ ions. Arch Biochem Biophys 199(2):420–426

    Article  CAS  Google Scholar 

  • Parker N, Affourtit C, Vidal-Puig A, Brand MD (2008) Energization-dependent endogenous activation of proton conductance in skeletal muscle mitochondria. Biochem J 412(1):131–139

    Article  CAS  Google Scholar 

  • Ravanel P, Tissut M, Douce R (1982) Effects of kaempferol on the oxidative properties of intact plant mitochondria. Plant Physiol 69(2):375–378

    Article  CAS  Google Scholar 

  • Rhein V, Giese M, Baysang G, Meier F, Rao S et al (2010) Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues abeta-induced failure. PLoS One 5(8):e12359

    Article  Google Scholar 

  • Sack MN (2006) Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res 72(2):210–219

    Article  CAS  Google Scholar 

  • Serrano-García N, Pedraza-Chaverri J, Mares-Sámano JJ, Orozco-Ibarra M, Cruz-Salgado A, Jiménez-Anguiano A, Sotelo J, Trejo-Solís C (2013) Antiapoptotic effects of EGb 761. Evid Based Complement Alternat Med Epub 2013 Jul 29

  • Shoshan-Barmatz V, Ben-Hail D (2012) VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion 12(1):24–34

    Article  CAS  Google Scholar 

  • Skemiene K, Rakauskaite G, Trumbeckaite S, Liobikas J, Brown GC, Borutaite V (2013) Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c. Int J Biochem Cell Biol 45(1):23–29

    Article  CAS  Google Scholar 

  • Skulachev VP (1998) Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1363(2):100–124

    Article  CAS  Google Scholar 

  • Szabò I, Leanza L, Gulbins E, Zoratti M (2012) Physiology of potassium channels in the inner membrane of mitochondria. Pflugers Arch 463(2):231–246

    Article  Google Scholar 

  • Tendi EA, Bosetti F, Dasgupta SF, Stella AM, Drieu K, Rapoport SI (2002) Ginkgo biloba extracts EGb 761 and bilobalide increase NADH dehydrogenase mRNA level and mitochondrial respiratory control ratio in PC12 cells. Neurochem Res 27(4):319–323

    Article  CAS  Google Scholar 

  • Toleikis A, Trumbeckaite S, Majiene D (2005) Cytochrome C effect on respiration of heart mitochondria: influence of various factors. Biosci Rep 25(5–6):387–397

    Article  CAS  Google Scholar 

  • Trumbeckaite S, Bernatoniene J, Majiene D, Jakstas V, Savickas A, Toleikis A (2006) The effect of flavonoids on rat heart mitochondrial function. Biomed Pharmacother 60(5):245–248

    Article  CAS  Google Scholar 

  • Trumbeckaite S, Bernatoniene J, Majiene D, Jakstas V, Savickas A, Toleikis A (2007) Effect of Ginkgo biloba extract on the rat heart mitochondrial function. J Ethnopharmacol 11(3):512–516

    Article  Google Scholar 

  • Wagner H, Ulrich-Merzenich G (2009) Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 16(2–3):97–110

    Article  CAS  Google Scholar 

  • Zheng J, Ramirez VD (1999) Piceatannol, a stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Biochem Biophys Res Commun 261(2):499–503

    Article  CAS  Google Scholar 

  • Zheng J, Ramirez VD (2000) Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol 130(5):1115–1123

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009, Kaunas, Lithuania

    Giedre Baliutyte, Sonata Trumbeckaite, Rasa Baniene, Vilmante Borutaite & Adolfas Toleikis

  2. Department of Pharmacognosy, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009, Kaunas, Lithuania

    Sonata Trumbeckaite

  3. Department of Biochemistry, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009, Kaunas, Lithuania

    Rasa Baniene

Authors
  1. Giedre Baliutyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonata Trumbeckaite
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rasa Baniene
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vilmante Borutaite
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adolfas Toleikis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rasa Baniene.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baliutyte, G., Trumbeckaite, S., Baniene, R. et al. Effects of standardized extract of Ginkgo biloba leaves EGb761 on mitochondrial functions: mechanism(s) of action and dependence on the source of mitochondria and respiratory substrate. J Bioenerg Biomembr 46, 493–501 (2014). https://doi.org/10.1007/s10863-014-9590-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-014-9590-8

Keywords

Search

Navigation