Skip to main content
SpringerLink
Log in

Involvement of the Mitochondrial Ca2+-Independent Phospholipase iPLA2 in the Induction of Mitochondrial Permeability Transition Pore by Long-Chain Acylcarnitines

  • Published:
Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

It is known that activated derivatives of long-chain fatty acids acylcarnitines (LCAC) are considered the most toxic, which, along with calcium, can participate in the induction of the mitochondrial pore, involving various types of phospholipases. In this study, the effect of inhibitors of Ca2+-independent and Ca2+-dependent phospholipases, as well as an inhibitor of carnitine palmitoyltransferase on the induction of pores with D,L-palmitoylcarnitine (PC, C16:0) was investigated. In experiments on isolated rat liver mitochondria, the effect of PC on mitochondrial respiration rate, membrane potential (ΔΨm) and mitochondrial swelling during oxidation of glutamate and pyruvate or succinate was studied. It was shown that inhibitors of carnitine palmitoyltransferase-1 etomoxir 2, Ca2+-dependent phospholipase cPLA2 aristolochic acid or Ca2+-independent phospholipase iPLA2γ bromoenol lactone and PACOCF3 caused an increase in critical concentrations of D,L-palmitoylcarnitine (PC*), which were required to decrease the membrane potential and induce mitochondrial swelling. In the ADP activated state 3 (ADP + Mg2+ + hexokinase), Ethomoxir 2 and aristolochic acid promoted the inhibition of respiration and dissipation of membrane potential caused by excess of PC, while phospholipase inhibitors iPLA2γ PACOCF3 and bromoenol lactone provided a pronounced protective effect. Inhibition of iPLA2γ prevented the decrease of ΔΨm and inhibition of respiration caused by PC. Thus, the results obtained indicated the involvement of mitochondrial phospholipase iPLA2γ in the induction of the mitochondrial pore by long-chain acylcarnitines.

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

  1. Hunter D.R., Haworth R.A. 1979. The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch. Biochem. Biophys. 195 (2), 468–477.

    Article  CAS  PubMed  Google Scholar 

  2. Crompton M., Ellinger H., Costi A. 1988. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem. J. 255, 357–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bernardi P., Broekemeir K.M., Pfeiffer D.R. 1994. Recent progress on regulation of the mitochondrial permeability transition pore; A cyclosporine-sensitive pore in the inner mitochondrial membrane. J. Bioenerg. Biomembr. 26 (5), 509–517. https://doi.org/10.1007/BF00762735

    Article  CAS  PubMed  Google Scholar 

  4. Kwong J.Q., Molkentin J.D. 2015. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab. 21 (2), 206. https://doi.org/10.1016/j.cmet.2014.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ford D.A., Han X., Horner C.C., Gross W. 1996. Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: Metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. Biochemistry. 35 (24), 7903. https://doi.org/10.1021/bi960552n

    Article  CAS  PubMed  Google Scholar 

  6. Lesnefsky E.J., Moghaddas S., Tandler B., Kerner J., Hoppel C.L. 2001. Mitochondrial dysfunction in cardiac disease: Ischemia–reperfusion, aging, and heart failure. J. Mol. Cell Cardiol. 33 (6), 1065–1089. https://doi.org/10.1006/jmcc.2001.1378

    Article  CAS  PubMed  Google Scholar 

  7. Koves T.R., Ussher J.R., Noland R.C., Slentz D., Mosedale M., Ilkayeva O., Bain J., Stevens R., Dyck J.R., Newgard C.B., Lopaschuk G.D., Muoio D.M. 2008. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7 (1), 45–56. https://doi.org/10.1016/j.cmet.2007.10.013

    Article  CAS  PubMed  Google Scholar 

  8. Fromenty B., Robin M.A., Igoudjil A., Mansouri A., Pessayre D. 2004. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 30 (2), 121–138. https://doi.org/10.1016/s1262-3636(07)70098-8

    Article  CAS  PubMed  Google Scholar 

  9. Liepinsh E., Makrecka-Kuka M., Volska K., Kuka J., Makarova E., Antone U., Sevostjanovs E., Vilskersts R., Strods A., Tars K., Dambrova M. 2016. Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria. Biochem. J. 473 (9), 1191–1202. https://doi.org/10.1042/BCJ20160164

    Article  CAS  PubMed  Google Scholar 

  10. Erfle J.D., Sauer F. 1969. The inhibitory effects of acyl-coenzyme A esters on the pyruvate and alpha-oxoglutarate dehydrogenase complexes. Biochim. Biophys. Acta. 178 (3), 441–452. https://doi.org/10.1016/0005-2744(69)90213-7

    Article  CAS  PubMed  Google Scholar 

  11. Lai J.C., Cooper A.J. 1991. Neurotoxicity of ammonia and fatty acids: Differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme A derivatives. Neurochem. Res. 16 (7), 795–803.

    Article  CAS  PubMed  Google Scholar 

  12. Farrell H.M. Jr, Wickham E.D., Reeves H.C. 1995. Effects of long-chain acyl-coenzyme A’s on the activity of the soluble form of nicotinamide adenine dinucleotide phosphate-specific isocitrate dehydrogenase from lactating bovine mammary gland. Arch. Biochem. Biophys. 321 (1), 199–208. https://doi.org/10.1006/abbi.1995.1386

    Article  CAS  PubMed  Google Scholar 

  13. Paulson D.J., Shug A.L. 1984. Inhibition of the adenine nucleotide translocator by matrix-localized palmityl-CoA in rat heart mitochondria. Biochim. Biophys. Acta. 766 (1), 70–76. https://doi.org/10.1016/0005-2728(84)90218-4.10

    Article  CAS  PubMed  Google Scholar 

  14. Schoënfeld P., Bohnensack R. 1997. Fatty acid-promoted mitochondrial permeability transition by membrane depolarization and binding to the ADP/ATP carrier. FEBS Letters. 420, 167–170.

    Article  Google Scholar 

  15. Ciapaite J., Van Eikenhorst D., Bakker S., Diamant M., Heine R.J., Wagner M.J., Westerhoff H.V., Krab K. 2005. Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. Diabetes. 54 (4), 944–951. https://doi.org/10.2337/diabetes.54.4.944

    Article  CAS  PubMed  Google Scholar 

  16. Wojtczak L., Wieckowski M.R. 1999. The mechanisMC of fatty acid-induced proton permeability of the inner mitochondrial membrane. J. Bioenerg. Biomembr. 31, 447–455.

    Article  CAS  PubMed  Google Scholar 

  17. Sultan A., Sokolove P.M. 2001. Palmitic acid opens a novel cyclosporin A-insensitive pore in the inner mitochondrial membrane. Arch. Biochem. Biophys. 386 (1), 37–51. https://doi.org/10.1006/abbi.2000.2194

    Article  CAS  PubMed  Google Scholar 

  18. Mironova G. D., Gateau-Roesch O., Levrat C., Gritsenko E., Pavlov E., Lazareva A.V., Limarenko E., Rey C., Louisot P., Saris N.E. 2001. Palmitic and stearic acids bind Ca2+ with high affinity and form nonspecific channels in black-lipid membranes. Possible relation to Ca2+-activated mitochondrial pores. J. Bioenerg. Biomembr. 33 (4), 319–331. https://doi.org/10.1023/a:1010659323937

    Article  CAS  PubMed  Google Scholar 

  19. Mironova G.D., Pavlov E.V. 2021. Mitochondrial cyclosporine A-independent palmitate/Ca2+-induced permeability transition pore (PA-mPT Pore) and its role in mitochondrial function and protection against calcium overload and glutamate toxicity. Cells. 10, 125. https://doi.org/10.3390/cells10010125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fedotcheva N.I., Grishina E.V., Dynnik V.V. 2022. Induction of mitochondrial cyclosporine-dependent pores by acylcarnitines. Influence of the concentration and length of the carbon chain. Biologicheskie membrany (Rus.). 39 (1), 75–82. https://doi.org/10.31857/S0233475522010066

  21. Dynnik V.V., Grishina E.V., Fedotcheva N.I. 2020. The mitochondrial NO-synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore. FEBS J. 287 (8), 1525–1536. https://doi.org/10.1111/febs.15090

    Article  CAS  PubMed  Google Scholar 

  22. Berezhnov A.V., Fedotova E.I., Nenov M.N., Kasymov V.A., Pimenov O.Y., Dynnik V.V. 2020. Dissecting cellular mechanisMC of long-chain acylcarnitines-driven cardiotoxicity: Disturbance of calcium homeostasis, activation of Ca2+-dependent phospholipases, and mitochondrial energetics collapse. Int. J. Mol. Sci. 21 (20), 7461. https://doi.org/10.3390/ijMC21207461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hollander J.M., Thapa D., Shepherd D.L. 2014. Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: Influence of cardiac pathologies. Am. J. Physiol. Circ. Physiol. 307, H1–H14. https://doi.org/10.1152/ajpheart.00747.2013

    Article  CAS  Google Scholar 

  24. Caro A.A., Cederbaum A.I. 2007. Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1. Arch. Biochem. Biophys. 457 (2), 252–263. https://doi.org/10.1016/j.abb.2006.10.018

    Article  CAS  PubMed  Google Scholar 

  25. Saito Y., Watanabe K., Fujioka D., Nakamura T., Obata J., Kawabata K., Watanabe Y., Mishina H., Tamaru S., Kita Y., Shimizu T., Kugiyama K. 2012. Disruption of group IVA cytosolic phospholipase A2 attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway. Am. J. Physiol. Circ. Physiol. 302, H2018–H2030. https://doi.org/10.1152/ajpheart.00955.2011

    Article  CAS  Google Scholar 

  26. Asemu G., Dhalla N.S., Tappia P.S. 2004. Inhibition of PLC improves postischemic recovery in isolated rat heart. Am. J. Physiol. Circ. Physiol. 287 (6), H2598–H2605. https://doi.org/10.1152/ajpheart.00506.2004

    Article  CAS  Google Scholar 

  27. Hara S., Yoda E., Sasaki Y., Nakatani Y., Kuwata H. 2019. Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases. Biochim. Biophys. Acta Mol. Cell. Biol. Lipids. 1864 (6), 861–868. https://doi.org/10.1016/j.bbalip.2018.10.009

  28. Moon S.H., Jenkins C.M., Liu X., Guan S., Mancuso D.J., Gross R.W. 2012. Activation of mitochondrial calcium-independent phospholipase A2γ (iPLA2γ) by divalent cations mediating arachidonate release and production of downstream eicosanoids. J. Biol. Chem. 287 (18), 14 880–14 895. https://doi.org/10.1074/jbc.M111.336776

    Article  CAS  Google Scholar 

  29. Kinsey G.R., Blum J.L., Covington M.D., Cummings B.S., McHowat J., Schnellmann R. 2008. Decreased iPLA-2gamma expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis. J. Lipid Res. 49 (7), 1477–1487. https://doi.org/10.1194/jlr.M800030-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kinsey G.R., McHowat J., Patrick K.S., Schnellmann R.G. 2007. Role of Ca2+-independent phospholipase A2gamma in Ca2+-induced mitochondrial permeability transition. J. Pharmacol. Exp. Ther. 321 (2), 707–715. https://doi.org/10.1124/jpet.107.119545

    Article  CAS  PubMed  Google Scholar 

  31. Rauckhorst A.J., Broekemeier K.M., Pfeiffer D.R. 2014. Regulation of the Ca2+-independent phospholipase A2 in liver mitochondria by changes in the energetic state. J. Lipid Res. 55 (5), 826–836. https://doi.org/10.1194/jlr.M043307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. WilliaMC S.D., Gottlieb R.A. 2002. Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective. Biochem. J. 362 (Pt 1), 23–32. https://doi.org/10.1042/0264-6021:3620023

    Article  Google Scholar 

  33. Moon S.H., Jenkins C.M., Kiebish M.A., SiMC H.F., Mancuso D.J., Gross R.W. 2012. Genetic ablation of calcium-independent phospholipase A(2)γ (iPLA(2)γ) attenuates calcium-induced opening of the mitochondrial permeability transition pore and resultant cytochrome c release. J. Biol. Chem. 287 (35), 29837–29850.https://doi.org/10.1074/jbc.M112.373654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moon S.H., Liu H., Cedars A.M., Yang C., Kiebish M.A., Joseph S.M., Kelley J., Jenkins C.M., Gross R.W. 2018. Heart failure-induced activation of phospholipase iPLA 2 γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. J. Biol. Chem. 293 (1), 115–129. https://doi.org/10.1074/jbc.RA117.000405

    Article  CAS  PubMed  Google Scholar 

  35. Moon S.H., Dilthey B.G., Liu X., Guan S., SiMC H.F., Gross R.W. 2021. High-fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress. J. Lipid Res. 62, 100052. https://doi.org/10.1016/j.jlr.2021.100052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dubinin M.V., Astashev M.E., Penkov N.V., Gudkov S.V., Dyachenko I.A., Samartsev V.N., Belosludtsev K.N. 2016. Effects of phospholipase A2 inhibitors on bilayer lipid membranes. J. Membr. Biol. 249 (3), 339–347. https://doi.org/10.1007/s00232-016-9872-7

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The work was performed under the State Contract 075-00381-21-00 of the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences (ITEB RAS).

Author information

Authors and Affiliations

  1. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow oblast, Russia

    N. I. Fedotcheva, E. V. Grishina & V. V. Dynnik

Authors
  1. N. I. Fedotcheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. V. Grishina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. V. Dynnik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. V. Dynnik.

Ethics declarations

The authors state that they have no conflict of interest.

The study was conducted in accordance with the ethical principles formulated in the Helsinki Declaration on the Use of Laboratory Animals and EU Directive 86/609/EEC. All procedures on animals were approved by the Ethics Committee of the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences (Protocol 19/2022, March 5, 2022).

Additional information

Translated by E. Puchkov

Publisher’s Note.

Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fedotcheva, N.I., Grishina, E.V. & Dynnik, V.V. Involvement of the Mitochondrial Ca2+-Independent Phospholipase iPLA2 in the Induction of Mitochondrial Permeability Transition Pore by Long-Chain Acylcarnitines. Biochem. Moscow Suppl. Ser. A 17, 325–331 (2023). https://doi.org/10.1134/S1990747823050045

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990747823050045

Keywords:

Search

Navigation