Bile Acids as Inducers of Protonophore and Ionophore Permeability of Biological and Artificial Membranes

It is now generally accepted that the role of bile acids in the organism is not limited to their participation in the process of food digestion. Indeed, bile acids are signaling molecules and being amphiphilic compounds, are also capable of modifying the properties of cell membranes and their organelles. This review is devoted to the analysis of data on the interaction of bile acids with biological and artificial membranes, in particular, their protonophore and ionophore effects. The effects of bile acids were analyzed depending on their physicochemical properties: namely the structure of their molecules, indicators of the hydrophobic–hydrophilic balance, and the critical micelle concentration. Particular attention is paid to the interaction of bile acids with the powerhouse of cells, the mitochondria. It is of note that bile acids, in addition to their protonophore and ionophore actions, can also induce Ca2+-dependent nonspecific permeability of the inner mitochondrial membrane. We consider the unique action of ursodeoxycholic acid as an inducer of potassium conductivity of the inner mitochondrial membrane. We also discuss a possible relationship between this K+ ionophore action of ursodeoxycholic acid and its therapeutic effects.

[1]  K. Belosludtsev,et al.  The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy , 2022, International journal of molecular sciences.

[2]  A. Elorza,et al.  Bile Acids Induce Alterations in Mitochondrial Function in Skeletal Muscle Fibers , 2022, Antioxidants.

[3]  Y. Antonenko,et al.  Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action , 2022, Acta naturae.

[4]  Huiping Zhou,et al.  Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids , 2022, Cells.

[5]  Xinchun Shen,et al.  A Review of Bile Acid Metabolism and Signaling in Cognitive Dysfunction-Related Diseases , 2022, Oxidative medicine and cellular longevity.

[6]  M. Camilleri Bile Acid Detergency: Permeability, Inflammation and Effects of Sulfation. , 2022, American journal of physiology. Gastrointestinal and liver physiology.

[7]  Tatyana V Butkova,et al.  A Recent Ten-Year Perspective: Bile Acid Metabolism and Signaling , 2022, Molecules.

[8]  M. Naud,et al.  Comparative Analysis of Urso- and Tauroursodeoxycholic Acid Neuroprotective Effects on Retinal Degeneration Models , 2022, Pharmaceuticals.

[9]  Wenxia Xu,et al.  Research Progress of Bile Acids in Cancer , 2022, Frontiers in Oncology.

[10]  P. Pinton,et al.  Molecular mechanisms and consequences of mitochondrial permeability transition , 2021, Nature Reviews Molecular Cell Biology.

[11]  Alessandra Del Giudice,et al.  Condensed Supramolecular Helices: The Twisted Sisters of DNA , 2021, Angewandte Chemie.

[12]  G. Lippe,et al.  The mitochondrial permeability transition: Recent progress and open questions , 2021, The FEBS journal.

[13]  N. Belosludtseva,et al.  Uridine treatment prevents myocardial injury in rat models of acute ischemia and ischemia/reperfusion by activating the mitochondrial ATP-dependent potassium channel , 2021, Scientific Reports.

[14]  G. Sukhikh,et al.  Neuroprotective Potential of Mild Uncoupling in Mitochondria. Pros and Cons , 2021, Brain sciences.

[15]  Alessandra Del Giudice,et al.  Revealing the complex self-assembly behaviour of sodium deoxycholate in aqueous solution. , 2021, Journal of colloid and interface science.

[16]  Edward Johnson,et al.  Exploring the therapeutic potential of mitochondrial uncouplers in cancer , 2021, Molecular metabolism.

[17]  G. Shulman,et al.  Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH , 2021, Molecular metabolism.

[18]  L. Galantini,et al.  Physiology and Physical Chemistry of Bile Acids , 2021, International journal of molecular sciences.

[19]  G. Mironova,et al.  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 , 2021, Cells.

[20]  P. P. Zagoskin,et al.  Bile Acids as a New Type of Steroid Hormones Regulating Nonspecific Energy Expenditure of the Body (Review) , 2020, Sovremennye tekhnologii v meditsine.

[21]  K. Belosludtsev,et al.  Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore , 2020, International journal of molecular sciences.

[22]  S. DeMorrow,et al.  Bile Acid Signaling in Neurodegenerative and Neurological Disorders , 2020, International journal of molecular sciences.

[23]  P. Pinton,et al.  Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology , 2020, Biomolecules.

[24]  M. Dubinin,et al.  A Comparative Study of the Action of Protonophore Uncouplers and Decoupling Agents as Inducers of Free Respiration in Mitochondria in States 3 and 4: Theoretical and Experimental Approaches , 2020, Cell Biochemistry and Biophysics.

[25]  E. Murphy,et al.  Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death. , 2020, Circulation research.

[26]  M. Dubinin,et al.  ω-Hydroxypalmitic and α,ω-Hexadecanedioic Acids As Activators of Free Respiration and Inhibitors of H2O2 Generation in Liver Mitochondria , 2020, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology.

[27]  Amy E. Chadwick,et al.  Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells , 2019, Toxicology in vitro : an international journal published in association with BIBRA.

[28]  C. Steer,et al.  Ursodeoxycholic acid: A promising therapeutic target for inflammatory bowel diseases? , 2019, American journal of physiology. Gastrointestinal and liver physiology.

[29]  Edward T Chouchani,et al.  H+ Transport is an Integral Function of the Mitochondrial ADP/ATP Carrier , 2019, Nature.

[30]  K. Belosludtsev,et al.  Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells , 2019, Biochemistry (Moscow).

[31]  P. Dawson,et al.  Animal models to study bile acid metabolism. , 2019, Biochimica et biophysica acta. Molecular basis of disease.

[32]  Luís M. S. Loura,et al.  Interaction of Bile Salts With Lipid Bilayers: An Atomistic Molecular Dynamics Study , 2019, Front. Physiol..

[33]  J. Geisler 2,4 Dinitrophenol as Medicine , 2019, Cells.

[34]  K. Belosludtsev,et al.  Induction of the Ca2+-Dependent Permeability Transition in Liver Mitochondria by α,ω-Hexadecanedioic Acid is Blocked by Inorganic Phosphate in the Presence of Cyclosporin A , 2019, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology.

[35]  Alessandra Del Giudice,et al.  Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles. , 2018, Langmuir : the ACS journal of surfaces and colloids.

[36]  M. Dubinin,et al.  Bile Acid-Induced Ca2+ Efflux from Liver Mitochondria as a Factor Preventing the Formation of Mitochondrial Pores , 2018, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology.

[37]  J. Chiang,et al.  Bile Acid Metabolism in Liver Pathobiology. , 2018, Gene expression.

[38]  J. Bard,et al.  Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells , 2018, Cellular Oncology.

[39]  J. Casadesús,et al.  Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts , 2017, Front. Med..

[40]  M. Dubinin,et al.  Lithocholic acid induces two different calcium-dependent inner membrane permeability systems in liver mitochondria , 2017, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology.

[41]  M. Dubinin,et al.  Ursodeoxycholic acid, in contrast to other bile acids, induces Ca2+-dependent cyclosporin A-insensitive permeability transition in liver mitochondria in the presence of potassium chloride , 2016, Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology.

[42]  R. Schubert,et al.  Membrane/Water Partition Coefficients of Bile Salts Determined Using Laurdan as a Fluorescent Probe. , 2016, Biophysical journal.

[43]  Tullio Pozzan,et al.  Enjoy the Trip: Calcium in Mitochondria Back and Forth. , 2016, Annual review of biochemistry.

[44]  Longkun Li,et al.  Hydrophobic bile acids relax rat detrusor contraction via inhibiting the opening of the Na+/Ca2+ exchanger , 2016, Scientific Reports.

[45]  M. Prieto,et al.  Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties[S] , 2015, Journal of Lipid Research.

[46]  E. Moghimipour,et al.  Absorption-Enhancing Effects of Bile Salts , 2015, Molecules.

[47]  P. Hylemon,et al.  Bile acids are nutrient signaling hormones , 2014, Steroids.

[48]  H. Jaeschke,et al.  Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice. , 2014, Toxicology letters.

[49]  S. Sollott,et al.  Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. , 2014, Physiological reviews.

[50]  M. Zoratti,et al.  Mitochondrial channels: ion fluxes and more. , 2014, Physiological reviews.

[51]  A. Walch,et al.  Progressive stages of mitochondrial destruction caused by cell toxic bile salts. , 2013, Biochimica et biophysica acta.

[52]  M. Cicala,et al.  Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. , 2013, World journal of gastroenterology.

[53]  V. Skulachev,et al.  Principles of Bioenergetics , 2012 .

[54]  C. Baines,et al.  Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. , 2012, The Biochemical journal.

[55]  Jianhua Zhang,et al.  Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling , 2011, The Biochemical journal.

[56]  V. Titorenko,et al.  Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells , 2011, Oncotarget.

[57]  J. Sastre,et al.  Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[58]  V. N. Samartsev,et al.  Free fatty acids as inducers and regulators of uncoupling of oxidative phosphorylation in liver mitochondria with participation of ADP/ATP- and aspartate/glutamate-antiporter , 2011, Biochemistry (Moscow).

[59]  D. Bourdette,et al.  Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons , 2011, The European journal of neuroscience.

[60]  J. Farber,et al.  Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. , 2010, The Journal of clinical investigation.

[61]  G. Gores,et al.  Hepatocyte death: a clear and present danger. , 2010, Physiological reviews.

[62]  S. Egelhaaf,et al.  Self-assembly in aqueous bile salt solutions , 2010 .

[63]  V. Skulachev,et al.  Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore , 2009, Proceedings of the National Academy of Sciences.

[64]  J. Marin,et al.  Bile acids: chemistry, physiology, and pathophysiology. , 2009, World journal of gastroenterology.

[65]  P. Bernardi,et al.  Phosphate Is Essential for Inhibition of the Mitochondrial Permeability Transition Pore by Cyclosporin A and by Cyclophilin D Ablation* , 2008, Journal of Biological Chemistry.

[66]  Yuan Zhao,et al.  Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge , 2007, J. Chem. Inf. Model..

[67]  A. Blume,et al.  Membranolytic activity of bile salts: influence of biological membrane properties and composition. , 2007, Molecules.

[68]  K. Belosludtsev,et al.  Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporin a-insensitive pore , 2007, Journal of bioenergetics and biomembranes.

[69]  C. Hill,et al.  The interaction between bacteria and bile. , 2005, FEMS microbiology reviews.

[70]  Samrat Mukhopadhyay,et al.  Chemistry and biology of bile acids , 2004 .

[71]  P. Oliveira,et al.  Chenodeoxycholate induction of mitochondrial permeability transition pore is associated with increased membrane fluidity and cytochrome c release: protective role of carvedilol. , 2003, Mitochondrion.

[72]  P. M. Sokolove,et al.  Palmitic acid opens a novel cyclosporin A-insensitive pore in the inner mitochondrial membrane. , 2001, Archives of biochemistry and biophysics.

[73]  P. Oliveira,et al.  Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[74]  P. Bernardi,et al.  Mitochondrial transport of cations: channels, exchangers, and permeability transition. , 1999, Physiological reviews.

[75]  G. Gores,et al.  Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases. , 1998, Biochimica et biophysica acta.

[76]  V. Skulachev Uncoupling: new approaches to an old problem of bioenergetics. , 1998, Biochimica et biophysica acta.

[77]  R. Moreno-Sánchez,et al.  On the Protection by Inorganic Phosphate of Calcium-Induced Membrane Permeability Transition , 1997, Journal of bioenergetics and biomembranes.

[78]  A. A. D’Archivio,et al.  Calcium Ion Binding to Bile Salts , 1997 .

[79]  A. V. Smirnov,et al.  Involvement of aspartate/glutamate antiporter in fatty acid-induced uncoupling of liver mitochondria. , 1997, Biochimica et biophysica acta.

[80]  M. Carey,et al.  Calcium affinity for biliary lipid aggregates in model biles: complementary importance of bile salts and lecithin. , 1994, Gastroenterology.

[81]  H. Westerhoff,et al.  Movement of fatty acids, fatty acid analogues, and bile acids across phospholipid bilayers. , 1993, Biochemistry.

[82]  P. Bernardi,et al.  Physiological effectors modify voltage sensing by the cyclosporin A-sensitive permeability transition pore of mitochondria. , 1993, The Journal of biological chemistry.

[83]  K. J. Mysels,et al.  Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions. , 1992, Journal of lipid research.

[84]  K. J. Mysels,et al.  Solubility of calcium salts of unconjugated and conjugated natural bile acids. , 1992, Journal of lipid research.

[85]  V. Skulachev Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation , 1991, FEBS letters.

[86]  D. Oelberg,et al.  Taurine-conjugated bile acids act as Ca2+ ionophores. , 1991, Biochemistry.

[87]  B. Hirst,et al.  Prostaglandin protects against bile salt induced increases in proton permeation of duodenal brush border membrane. , 1991, Gut.

[88]  V. Skulachev,et al.  Inhibitors of the ATP/ADP antiporter suppress stimulation of mitochondrial respiration and H+ permeability by palmitate and anionic detergents , 1990, FEBS letters.

[89]  A. Roda,et al.  Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. , 1990, Journal of lipid research.

[90]  H. Terada Uncouplers of oxidative phosphorylation. , 1990, Environmental health perspectives.

[91]  P. Schönfeld,et al.  Does the function of adenine nucleotide translocase in fatty acid uncoupling depend on the type of mitochondria? , 1990, FEBS letters.

[92]  V. Skulachev,et al.  The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. , 1989, European journal of biochemistry.

[93]  D. Oelberg,et al.  Effect of Bile Acids on Calcium Efflux from Isolated Rat Hepatocytes and Perfused Rat Livers , 1989, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[94]  D. Heuman Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. , 1989, Journal of lipid research.

[95]  M. Anwer,et al.  Bile acids increase cellular free calcium in cultured kidney cells (LLC-PK1) , 1988, Pflügers Archiv.

[96]  L. Combettes,et al.  Release of calcium from the endoplasmic reticulum by bile acids in rat liver cells. , 1988, The Journal of biological chemistry.

[97]  A. Roda,et al.  Chemical properties of bile acids. IV. Acidity constants of glycine-conjugated bile acids. , 1987, Journal of lipid research.

[98]  D. Oelberg,et al.  Bile salts induce calcium uptake in vitro by human erythrocytes , 1987, Hepatology.

[99]  J. Sunamoto,et al.  Bile salt damage of egg phosphatidylcholine liposomes. , 1985, Biochimica et biophysica acta.

[100]  A. Hofmann,et al.  Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. , 1984, Journal of lipid research.

[101]  D. Oelberg,et al.  Calcium binding by lithocholic acid derivatives. , 1984, The American journal of physiology.

[102]  J. Schölmerich,et al.  Influence of Hydroxylation and Conjugation of Bile Salts on Their Membrane‐Damaging Properties‐Studies on Isolated Hepatocytes and Lipid Membrane Vesicles , 1984, Hepatology.

[103]  A. Shamoo,et al.  Anionic detergents as divalent cation ionophores across black lipid membranes , 1979, The Journal of Membrane Biology.

[104]  J. K. Thomas,et al.  Kinetic studies in bile acid micelles. , 1975, Journal of the American Chemical Society.

[105]  S. Schryver Some investigations on the phenomena of "clot" formations. Part I.―On the clotting of milk , 1913 .

[106]  Harpreet Singh,et al.  Anion Channels of Mitochondria. , 2017, Handbook of experimental pharmacology.

[107]  J. Sastre,et al.  Mitochondrial dysfunction in cholestatic liver diseases. , 2012, Frontiers in bioscience.

[108]  P. Oliveira,et al.  Bile acids are toxic for isolated cardiac mitochondria , 2007, Cardiovascular Toxicology.

[109]  G. Forsyth,et al.  Ricinoleate and deoxycholate are calcium ionophores in jejunal brush border vesicles , 2005, The Journal of Membrane Biology.

[110]  Marianne,et al.  Ion Transport by Heart Mitochondria , 2003 .

[111]  D. Oelberg,et al.  Bile salt-induced calcium fluxes in artificial phospholipid vesicles. , 1988, Biochimica et biophysica acta.

[112]  M. Armstrong,et al.  The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities. , 1982, Journal of lipid research.

[113]  G. Hunt,et al.  A 1H-NMR investigation of the mechanism for the ionophore activity of the bile salts in phospholipid vesicular membranes and the effect of cholesterol. , 1980, Biochimica et biophysica acta.