The Short-Term Opening of Cyclosporin A-Independent Palmitate/Sr-Induced Pore Can Underlie Ion Efflux in the Oscillatory Mode of Functioning of Rat Liver Mitochondria

Overview

Journal Membranes (Basel)

Date 2022 Jul 25

PMID 35877870

Authors

Natalia V Belosludtseva

Lyubov L Pavlik

Konstantin N Belosludtsev

Nils-Erik L Saris

Maria I Shigaeva

Galina D Mironova

Affiliations

Soon will be listed here.

Abstract

Mitochondria are capable of synchronized oscillations in many variables, but the underlying mechanisms are still unclear. In this study, we demonstrated that rat liver mitochondria, when exposed to a pulse of Sr ions in the presence of valinomycin (a potassium ionophore) and cyclosporin A (a specific inhibitor of the permeability transition pore complex) under hypotonia, showed prolonged oscillations in K and Sr fluxes, membrane potential, pH, matrix volume, rates of oxygen consumption and HO formation. The dynamic changes in the rate of HO production were in a reciprocal relationship with the respiration rate and in a direct relationship with the mitochondrial membrane potential and other indicators studied. The pre-incubation of mitochondria with Ca(Sr)-dependent phospholipase A inhibitors considerably suppressed the accumulation of free fatty acids, including palmitic and stearic acids, and all spontaneous Sr-induced cyclic changes. These data suggest that the mechanism of ion efflux from mitochondria is related to the opening of short-living pores, which can be caused by the formation of complexes between Sr(Ca) and endogenous long-chain saturated fatty acids (mainly, palmitic acid) that accumulate due to the activation of phospholipase A by the ions. A possible role for transient palmitate/Ca(Sr)-induced pores in the maintenance of ion homeostasis and the prevention of calcium overload in mitochondria under pathophysiological conditions is discussed.

Citing Articles

Protective Effect of Uridine on Structural and Functional Rearrangements in Heart Mitochondria after a High-Dose Isoprenaline Exposure Modelling Stress-Induced Cardiomyopathy in Rats.

Belosludtseva N, Pavlik L, Mikheeva I, Talanov E, Serov D, Khurtin D Int J Mol Sci. 2023; 24(24).

PMID: 38139129 PMC: 10744270. DOI: 10.3390/ijms242417300.

References

Kravenska Y, Checchetto V, Szabo I . Routes for Potassium Ions across Mitochondrial Membranes: A Biophysical Point of View with Special Focus on the ATP-Sensitive K Channel. Biomolecules. 2021; 11(8). PMC: 8393992. DOI: 10.3390/biom11081172. View

Mironova G, Belosludtsev K, Belosludtseva N, Gritsenko E, Khodorov B, Saris N . Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporin A-insensitive pore. J Bioenerg Biomembr. 2007; 39(2):167-74. DOI: 10.1007/s10863-007-9079-9. View

Kargapolov A . [Changes in the phospholipid content of intact mitochondria under mitochondrial swelling in hypotonic sucrose solutions]. Biokhimiia. 1979; 44(2):293-6. View

Briston T, Selwood D, Szabadkai G, Duchen M . Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets. Trends Pharmacol Sci. 2018; 40(1):50-70. DOI: 10.1016/j.tips.2018.11.004. View

Mironova G, Saris N, Belosludtseva N, Agafonov A, Elantsev A, Belosludtsev K . Involvement of palmitate/Ca2+(Sr2+)-induced pore in the cycling of ions across the mitochondrial membrane. Biochim Biophys Acta. 2014; 1848(2):488-95. DOI: 10.1016/j.bbamem.2014.10.027. View

Samanta K, Mirams G, Parekh A . Sequential forward and reverse transport of the Na Ca exchanger generates Ca oscillations within mitochondria. Nat Commun. 2018; 9(1):156. PMC: 5765001. DOI: 10.1038/s41467-017-02638-2. View

Kotova E, Antonenko Y . Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action. Acta Naturae. 2022; 14(1):4-13. PMC: 9013436. DOI: 10.32607/actanaturae.11610. View

Buckman J, Reynolds I . Spontaneous changes in mitochondrial membrane potential in cultured neurons. J Neurosci. 2001; 21(14):5054-65. PMC: 6762873. View

Aon M, Cortassa S, ORourke B . Mitochondrial oscillations in physiology and pathophysiology. Adv Exp Med Biol. 2008; 641:98-117. PMC: 2692514. DOI: 10.1007/978-0-387-09794-7_8. View

10.

GARLID K, Paucek P . The mitochondrial potassium cycle. IUBMB Life. 2002; 52(3-5):153-8. DOI: 10.1080/15216540152845948. View

11.

Agafonov A, Gritsenko E, Shlyapnikova E, Kharakoz D, Belosludtseva N, Lezhnev E . Ca2+-induced phase separation in the membrane of palmitate-containing liposomes and its possible relation to membrane permeabilization. J Membr Biol. 2007; 215(1):57-68. DOI: 10.1007/s00232-007-9005-4. View

12.

Kirichok Y, Krapivinsky G, Clapham D . The mitochondrial calcium uniporter is a highly selective ion channel. Nature. 2004; 427(6972):360-4. DOI: 10.1038/nature02246. View

13.

Belosludtsev K, Saris N, Belosludtseva N, Trudovishnikov A, Lukyanova L, Mironova G . Physiological aspects of the mitochondrial cyclosporin A-insensitive palmitate/Ca2+-induced pore: tissue specificity, age profile and dependence on the animal's adaptation to hypoxia. J Bioenerg Biomembr. 2009; 41(4):395-401. DOI: 10.1007/s10863-009-9230-x. View

14.

Belosludtsev K, Belosludtseva N, Talanov E, Tenkov K, Starinets V, Agafonov A . Effect of bedaquiline on the functions of rat liver mitochondria. Biochim Biophys Acta Biomembr. 2018; 1861(1):288-297. DOI: 10.1016/j.bbamem.2018.06.012. View

15.

Ghosh M, Loper R, Gelb M, Leslie C . Identification of the expressed form of human cytosolic phospholipase A2beta (cPLA2beta): cPLA2beta3 is a novel variant localized to mitochondria and early endosomes. J Biol Chem. 2006; 281(24):16615-24. DOI: 10.1074/jbc.M601770200. View

16.

Lepage G, Roy C . Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res. 1986; 27(1):114-20. View

17.

Murakami M, Sato H, Taketomi Y . Updating Phospholipase A Biology. Biomolecules. 2020; 10(10). PMC: 7603386. DOI: 10.3390/biom10101457. View

18.

Belosludtsev K, Dubinin M, Belosludtseva N, Mironova G . Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochemistry (Mosc). 2019; 84(6):593-607. DOI: 10.1134/S0006297919060026. View

19.

Wacquier B, Combettes L, Tran van Nhieu G, Dupont G . Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism. Sci Rep. 2016; 6:19316. PMC: 4725975. DOI: 10.1038/srep19316. View

20.

Mironova G, Gateau-Roesch O, Levrat C, Gritsenko E, Pavlov E, Lazareva A . 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. 2001; 33(4):319-31. DOI: 10.1023/a:1010659323937. View