Ukr.Biochem.J. 2013; Volume 85, Issue 3, May-Jun, pp. 38-51


The effect of ATP-dependent K(+)-channel opener on the functional state and the opening of cyclosporine-sensitive pore in rat liver mitochondria

O. V. Akopova, V. I. Nosar, V. A. Bouryi, L. I. Kolchinskaya,
I. N. Mankovska, V. F. Sagach

Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv;

The effect of mitochondrial ATP-dependent K+-channel (K+АТР-channel) opener diazoxide (DZ) on the oxygen consumption, functional state and the opening of cyclosporine-sensitive pore in the rat liver mitochondria has been studied. It has been established that K+АТР-channel activation results in the increase of the oxygen consumption rate (V4S) and the uncoupling due to the acceleration of K+-cycling, the decrease in state 3 respiration rate (V3) and the respiratory control ratio (RCR). Under K+АТР-channel activation an inhibition of oxidative phosphorylation takes place which reduces the rate of ATP synthesis and hydrolysis as well as ATP production and consequently results in the seeming increase of P/O ratio. It has been shown that the increase in ATP-dependent K+-uptake accompanied by the opening of mitochondrial permeability transition pore (MPTP) leads to dramatic uncoupling of the respiratory chain due to simultaneous activation of K+– and Ca2+-cycling supported by MPTP and Ca2+-uniporter as well as K+-channels and K+/H+-exchange. K+АТР-channel activation leads to the partial inhibition of MPTP, but insufficient for the restoration of mitochondrial functions. Elimination of Ca2+-cycling after MPTP opening is necessary to return mitochondrial functions back to the control level which shows that MPTP could serve as the mechanism of reversible modulation of bioenergetic effects of K+АТР-channel activation.

Keywords: , , , , ,


  1. Inoue I, Nagase H, Kishi K, Higuti T. ATP-sensitive K+ channel in the mitochondrial inner membrane. Nature. 1991 Jul 18;352(6332):244-7. PubMedCrossRef
  2. Mironova GD, Kachayeva YeV, Krylova IB, Rodionova ОМ, Balina MI, Yevdokimova NR, Sapronov NS. Mitochondrial ATP-dependent potassium channel. 2. The role of the channel in protection of the heart against ischemia. Vestn Ross Akad Med Nauk. 2007;(2):44-50. PubMed
  3. Facundo HT, de Paula JG, Kowaltowski AJ. Mitochondrial ATP-sensitive K+ channels prevent oxidative stress, permeability transition and cell death. J Bioenerg Biomembr. 2005 Apr;37(2):75-82. PubMed, CrossRef
  4. Oldenburg O, Cohen MV, Yellon DM, Downey JM. Mitochondrial K(ATP) channels: role in cardioprotection. Cardiovasc Res. 2002 Aug 15;55(3):429-37. PubMed, CrossRef
  5. O’Rourke B. Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res. 2004 Mar 5;94(4):420-32. PubMedPubMedCentral, CrossRef
  6.  Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition.  Physiol Rev. 1999 Oct;79(4):1127-55. PubMed
  7. Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961 Jul 8(4784);191:144-8. PubMedCrossRef
  8.  Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004 Oct;287(4):C817-33. PubMed, CrossRef
  9. Beavis AD. Upper and lower limits of the charge translocation stoichiometry of mitochondrial electron transport. J Biol Chem. 1987 May 5;262(13):6165-73. PubMed
  10.  Beavis AD, Lehninger AL. The upper and lower limits of the mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Stoichiometry of oxidative phosphorylation. Eur J Biochem. 1986 Jul 15;158(2):315-22.  PubMed, CrossRef
  11.   Skulachev VP. Transformation of energy in biological membranes. M.: Nauka, 1972. 203 p.
  12. Garlid KD, Paucek P. Mitochondrial potassium transport: the K(+) cycle. Biochim Biophys Acta. 2003 Sep 30;1606(1-3):23-41. PubMedCrossRef
  13. Miwa S, Brand MD. Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans. 2003 Dec;31(Pt 6):1300-1. PubMed, CrossRef
  14. Stucki JW. Efficiency of oxidative phosphorylation and energy dissipation by H+ ion recycling in rat-liver mitochondrial metabolizing pyruvate. Eur J Biochem. 1976 Sep 15;68(2):551-62. PubMedCrossRef
  15. Liu SS. Cooperation of a “reactive oxygen cycle” with the Q cycle and the proton cycle in the respiratory chain–superoxide generating and cycling mechanisms in mitochondria. J Bioenerg Biomembr. 1999 Aug;31(4):367-76. PubMed
  16.  Skulachev VP. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med. 1999 Jun;20(3):139-84. PubMed, CrossRef
  17.  Kroemer G, Reed JC. Mitochondrial control of cell death.  Nat Med. 2000 May;6(5):513-9. PubMed, CrossRef
  18.  Holmuhamedov EL, Jovanović S, Dzeja PP, Jovanović A, Terzic A. Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function. Am J Physiol. 1998 Nov;275(5 Pt 2):H1567-76. PubMed
  19.  Murata M, Akao M, O’Rourke B, Marbán E. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection. Circ Res. 2001 Nov 9;89(10):891-8. PubMedCrossRef
  20. Facundo HT, Fornazari M, Kowaltowski AJ. Tissue protection mediated by mitochondrial K+ channels. Biochim Biophys Acta. 2006 Feb;1762(2):202-12. PubMedCrossRef
  21. Costa AD, Garlid KD. Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT. Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H874-82. PubMed, PubMedCentral, CrossRef
  22.  Korge P, Honda HM, Weiss JN. Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning. Proc Natl Acad Sci USA. 2002 Mar 5;99(5):3312-7.  PubMedPubMedCentralCrossRef
  23. Costa AD, Quinlan CL, Andrukhiv A, West IC, Jabůrek M, Garlid KD. The direct physiological effects of mitoK(ATP) opening on heart mitochondria.  Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H406-15. PubMed, CrossRef
  24.  Akopova OV, Nosar VI, Bouryi VA, Mankovskaya IN, Sagach VF. Influence of ATP-dependent K+-channel opener on K+-cycle and oxygen consumption in rat liver mitochondria. Biochemistry (Mosc). 2010 Sep;75(9):1139-47. PubMedCrossRef
  25.  Akopova OV. The influence of ATP-dependent K+-channel diazoxide opener on the opening of mitochondrial permeability transition pore in rat liver mitochondria.  Ukr Biokim Zhurn. 2011 May-Jun;83(3):37-47. PubMed
  26. Cancherini DV, Trabuco LG, Rebouças NA, Kowaltowski AJ. ATP-sensitive K+ channels in renal mitochondria.  Am J Physiol Renal Physiol. 2003 Dec;285(6):F1291-6.
  27.  Cockrell RS. Ruthenium red-insensitive Ca2+ uptake and release by mitochondria. Arch Biochem Biophys. 1985 Nov 15;243(1):70-9. PubMed
  28. Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. The mitochondrial KATP channel as a receptor for potassium channel openers. J Biol Chem. 1996 Apr 12;271(15):8796-9. PubMed, CrossRef
  29. The membranes: ion channels.  Coll. art. Ed. Yu. A. Chizmadzhev. M.:Mir, 1981. 320 p.
  30. Mitchell P, Moyle J. Proton translocation coupled to ATP hydrolysis in rat liver mitochondria. Eur J Biochem. 1968 May;4(4):530-9. PubMedCrossRef
  31.  Hinkle PC, Yu ML. The phosphorus/oxygen ratio of mitochondrial oxidative phosphorylation. J Biol Chem. 1979 Apr 10;254(7):2450-5. PubMed
  32. Comelli M, Metelli G, Mavelli I. Downmodulation of mitochondrial F0F1 ATP synthase by diazoxide in cardiac myoblasts: a dual effect of the drug. Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H820-9. PubMedCrossRef
  33. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol. 2001 Feb;280(2):H649-57. PubMed
  34.  Rottenberg H, Koeppe RE. Mechanism of uncoupling of oxidative phosphorylation by gramicidin. Biochemistry. 1989 May 16;28(10):4355-60. PubMedCrossRef
  35. Solodovnikova IM, Iurkov VI, Ton’shin AA, Yaguzhinsky LS. Local coupling of respiration processes and phosphorylation in rat liver mitochondria. Biofizika. 2004 Jan-Feb;49(1):47-56. Russian. PubMed
  36. Krasinskaya IP, Korshunov SS, Kachanov OYu, Yaguzhinsky LS. The immobilized matrix buffer controls the rate of mitochondrial respiration in state 3P according to chance. Biochemistry (Mosc). 1997 Apr;62(4):364-70. PubMed
  37. Akopova OV. The role of mitochondrial permeability transition pore in transmembrane Ca2+-exchange in mitochondria. Ukr Biokhim Zhurn. 2008 May-Jun;80(3):40-7. Ukrainian. PubMed
  38. Nogueira V, Devin A, Walter L, Rigoulet M, Leverve X, Fontaine E. Effects of decreasing mitochondrial volume on the regulation of the permeability transition pore. J Bioenerg Biomembr. 2005 Feb;37(1):25-33. PubMedCrossRef
  39. Halestrap AP, Kerr PM, Javadov S, Woodfield KY. Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart. Biochim Biophys Acta. 1998 Aug 10;1366(1-2):79-94. PubMedCrossRef

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