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Samartsev, V.N.; Khoroshavina, E.I.; Pavlova, E.K.; Dubinin, M.V.; Semenova, A.A. Protonophore and Ionophore Effects of Bile Acids. Encyclopedia. Available online: https://encyclopedia.pub/entry/45254 (accessed on 16 November 2024).
Samartsev VN, Khoroshavina EI, Pavlova EK, Dubinin MV, Semenova AA. Protonophore and Ionophore Effects of Bile Acids. Encyclopedia. Available at: https://encyclopedia.pub/entry/45254. Accessed November 16, 2024.
Samartsev, Victor N., Ekaterina I. Khoroshavina, Evgeniya K. Pavlova, Mikhail V. Dubinin, Alena A. Semenova. "Protonophore and Ionophore Effects of Bile Acids" Encyclopedia, https://encyclopedia.pub/entry/45254 (accessed November 16, 2024).
Samartsev, V.N., Khoroshavina, E.I., Pavlova, E.K., Dubinin, M.V., & Semenova, A.A. (2023, June 06). Protonophore and Ionophore Effects of Bile Acids. In Encyclopedia. https://encyclopedia.pub/entry/45254
Samartsev, Victor N., et al. "Protonophore and Ionophore Effects of Bile Acids." Encyclopedia. Web. 06 June, 2023.
Protonophore and Ionophore Effects of Bile Acids
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This entry is adapted from the peer-reviewed paper 10.3390/membranes13050472

Bile acids are signaling molecules and being amphiphilic compounds, are also capable of modifying the properties of cell membranes and their organelles.

bile acids membranes mitochondria

1. Introduction

Bile acids and their salts form the basis of bile in higher vertebrates and humans. As part of bile, they play an important role in the process of digestion of food; their main physiological function is to emulsify bile lipids, in particular cholesterol. Emulsification of lipids by bile acids facilitates the absorption of fat-soluble vitamins and calcium in the intestine, and the digestion of triglycerols. In addition, bile excretion is necessary to eliminate toxins, carcinogens, as well as drugs and their metabolites. Apart from cholesterol, other endogenous compounds and metabolic products, such as bilirubin and hormones, are also excreted along with bile [1][2].
Bile acids are well known to be effective antimicrobial agents preventing the growth of bacteria in the small intestine [1][3][4]. Currently, the role of bile acids as signaling molecules regulating various metabolic pathways in cells is also being considered [2][5][6][7][8][9].
Primary bile acids—chenodeoxycholic (CDCA) and cholic (CA)—are synthesized from cholesterol in parenchymal cells (hepatocytes) of the liver of mammals and humans. In rodents, due to alternative hydroxylation, the formation of other primary bile acids is also possible, in particular, α-, β-, and γ-muricholic acids. Secondary bile acids are formed from these bile acids in the intestine with the participation of bacteria—lithocholic acid (LCA)-from CDCA, deoxycholic acid (DCA)-from CA. Additionally, in the intestine, ursodeoxycholic acid (UDCA) is formed from CDCA by epimeration of the hydroxyl group at the seventh carbon atom of the steroid nucleus (transfer of the hydroxyl group from the α-surface to the β-surface).
Bile acids are considered as endogenous detergents. In particular, when interacting with artificial and biological membranes in concentrations exceeding their critical micelle concentration, bile acids cause profound disturbances in their structure and function, up to their permeabilization and lysis. It is of note that hydrophobic bile acids are most effective in this case [10][11][12][13]. The protonophore [14][15] and ionophore [16][17][18] effects of bile acids are also known (see the next section for more details).
In cholestasis caused by a blockage of the outflow of bile from the liver, the cells of this organ and the blood show first of all the accumulation of primary bile acids-CDCA and CA [19][20]. At concentrations characteristic of cholestasis, hydrophobic bile acids can solubilize lipids of cell membranes of hepatocytes leading to their damage and, in particular, to the release of γ-glutamyl transpeptidase from cells, whose increase in serum levels is a diagnostic sign of cholestasis [21]. In the course of chronic cholestasis, there is a violation of calcium homeostasis in hepatocytes and the release of calcium ions from the main depots—the endoplasmic reticulum and mitochondria. In this case, monohydroxy bile acids primarily release Ca2+ from the endoplasmic reticulum in the liver [22].
It is well known that hydrophobic bile acids, both primary CDCA and secondary LCA and DCA, as well as their glycine and taurine conjugates, have pronounced cytotoxicity [23][24][25]. LCA has been shown to selectively cause cell death in some malignant neoplasms [23][26]. Unlike other bile acids, UDCA is considered as a drug in the treatment of liver diseases and some other pathologies [27][28][29].
Several types of cell death are known, differing both in morphological features and in biochemical mechanisms. However, in all cases, the central role in these processes is assigned to mitochondria, which integrate many intracellular signaling pathways leading to cell death [24][30][31][32]. It is now generally accepted that one of the links in cell death associated with mitochondria is the opening of a Ca2+-dependent mitochondrial permeability transition pore (MPT-pore) in the inner membrane of these organelles for ions and hydrophilic substances, whose mass does not exceed 1.5 kDa, along their concentration gradient [33][34][35][36][37].
Bile acids have a variety of effects on the mitochondria of vital mammalian organs; they inhibit electron transport along the respiratory chain, induce a decrease on state 3 respiration, the respiratory control ratio, and the membrane potential and cause the induction of the MPT-pore [38][39][40][41][42][43][44][45][46].

2. Physico-Chemical Characteristics of Bile Acids

Bile acids are a family of amphiphilic molecules containing a hydrophilic carboxyl group and a hydrophobic steroid structure (steroid core) with a different number of hydroxyl groups. The steroid core is considered as a flat structure with two surfaces depending on the localization of the hydroxyl groups—a more hydrophobic convex β-surface and a more hydrophilic concave α-surface.
Bile acids, being amphiphilic compounds, like other similar amphiphilic compounds, are detergents. However, bile acids differ significantly from classical detergents [12][47][48][49]. In classical amphiphiles, in particular lipids, the hydrophilic head consists of relatively small polar or charged groups, and the hydrophobic tails are often long, flexible, and non-polar hydrocarbon chains. Bile salts show other features. The polar hydroxyl groups are oriented towards the concave side of the rigid steroid ring system, which thus becomes hydrophilic, while the convex side is hydrophobic [1][12][47][48][49]. Thus, bile salts have a face structure with hydrophobic and hydrophilic sides or, depending on the position and orientation of the hydroxyl groups, a hydrophilic ‘edge’ only. Consequently, the hydrophilic and hydrophobic domains are not as clearly separated as is typical for classical amphiphiles. In addition, the hydrophobic tails of common amphiphiles inside the micellar core are liquid-like, while the steroid ring system is very rigid [1][12][47][48][49]. The hydrophobic–hydrophilic balance of bile acids as well as other amphiphilic compounds can be quantified as the partition coefficient between the lipid and aqueous phases (P or logP). The lower the value of this coefficient, the less hydrophobic and, therefore, more hydrophilic is the bile acid. As can be seen from the table, the values of this coefficient differ significantly depending on the method of their determination. However, depending on the structure of the bile acid molecule (the number of hydroxyl groups), the values of these coefficients show that monohydroxyl LCA is the most hydrophobic, dihydroxyl DCA, CDCA, and UDCA are less hydrophobic, and trihydroxyl cholic acid is the least hydrophobic. As follows from the data in the table, the hydrophobicity of glycine and taurine conjugates is significantly less than the corresponding non-conjugated acids.
Like amphiphilic compounds, bile acids are capable of self-organization with the formation of micelles when their concentration in water is increased to a certain level [47][50][51][52]. This extreme concentration of bile acids is called the critical micelle concentration (CMC) [47][49][50][51]. Bile acids can form either primary or secondary micelles. Primary bile acid micelles have aggregation numbers from 2 to 10 and are formed via hydrophobic interactions, while secondary micelles (aggregation numbers 10–100) are formed via hydrogen bonding interactions of the primary micellar structures [47][48][49]. The pH at which CMC formation occurs is called the critical micellar pH at which the solubility increases markedly [50].

3. Effect of Bile Acids on the Permeability of Biological and Artificial Phospholipid Membranes for Protons and Ions

3.1. Protonophore Action of Bile Acids

As mentioned above, free (non-conjugated) bile acids are weak acids. A large number of weak organic acids are known to be effective protonophore uncouplers of oxidative phosphorylation in animal mitochondria [53][54][55][56]. Among them, the mechanism of the uncoupling action of classical protonophore uncouplers (2,4-dinitrophenol or DNP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, or FCCP, etc.) has been well studied. These uncouplers, by increasing the proton conductivity of the inner mitochondrial membrane and thus dissipating the proton motive force (Δp), stimulate respiration and reduce the efficiency of oxidative ATP synthesis (reduce the ADP/O and respiratory control ratios) [57][58].
Perhaps the most fully studied natural protonophore uncouplers of oxidative phosphorylation are free monocarboxylic fatty acids [53][59][60][61][62][63][64]. It has been established that carrier proteins of the inner mitochondrial membrane that carry out the exchange transport of ADP to ATP (ADP/ATP-antiporter) are involved in the uncoupling effect of monocarboxylic fatty acids in mitochondria of vital organs of mammals (heart, liver, kidneys, skeletal muscles) [57][62][64][65][66][67].
The protonophore effect of bile acids was studied both on model membrane systems [15] and on isolated mitochondria [38][41][68]. Hamilton’s laboratory [15] studied the permeability of membranes for fatty and bile acids in experiments with liposomes loaded with the fluorescent pH indicator pyranine. It was found that after the addition of bile acids—CA, DCA, CDCA—to a suspension of liposomes, their neutral molecules are able to move from the outer monolayer of the membrane to the inner one (flip-flop).
Non-conjugated bile acids (LCA, CDCA, DCA) are considered as effective uncouplers of oxidative phosphorylation [38]. These bile acids have been shown to stimulate respiration in state 4 and reduce respiratory control and membrane potential (Δψ) of succinate-fueled liver mitochondria. The most hydrophobic LCA showed the strongest effect. The less hydrophobic chenodeoxycholic and deoxycholic acids were less effective. It should be noted that the hydrophobicity of UDCA is the same as that of CDCA and DCA, but its effectiveness as an uncoupler of oxidative phosphorylation is significantly inferior to these two bile acids [38]. Hydrophilic taurine and glycine conjugates of these bile acids were significantly less effective [38] despite their lower CMC.
Based on these data and by analogy with the uncoupling effect of fatty acids (see above), the following hypothetical scheme can be proposed (Figure 1). It is assumed that free (non-conjugated) anions are protonated on the outer surface of the inner mitochondrial membrane, since their pKa on the membrane surface is 2.5 units higher than in an aqueous solution [69] and, therefore, its value is 7.5. Further, neutral molecules of bile acids are transported through the phospholipid bilayer to the opposite side of the membrane by the flip-flop mechanism, followed by the release of a proton into the mitochondrial matrix. The transport of the bile acid anion in the opposite direction is carried out with the assistance of the ADP/ATP antiporter. At the same time, it cannot be ruled out that the effects of bile acids described above may be due to damage to the inner mitochondrial membrane, as was suggested for the nonionic detergent Triton X-100 and the cationic detergent cetyltrimethylammonium bromide [68].
/media/item_content/202306/64814a0d7445dmembranes-13-00472-g002.png
Figure 1. Hypothetical scheme illustrating the transport of protons by bile acid across the inner membrane of liver mitochondria with the participation of the ADP/ATP-antiporter (AAA). According to this scheme, the bile acid anion (symbol (−)) is protonated on the outer surface of the inner membrane (step 1). The neutral bile acid molecule (symbol (H)) is transported across the phospholipid bilayer to the opposite side of the membrane by the flip-flop mechanism (step 2). This stage is fast [15] and does not require any carrier. During this stage, protons are transported from a more acidic compartment (membrane space) to a more alkaline one (matrix). On the inner surface of the inner membrane, a neutral bile acid molecule releases a proton into the matrix (deprotonates) to form a bile acid anion (step 3). The bile acid anion moves in the opposite direction with the participation of the ADP/ATP-antiporter (step 4). This step 4 is electrogenic since energy in the form of ΔΨ is expended to move the anion.

3.2. Ionophore Action of Bile Acids

It is well known that many bile acids have a relatively high affinity for Ca2+ [70][71][72][73][74][75]. High concentrations of Ca2+ (2.5–5 mM) and bile acids (2–5 mM) are able to form micellar aggregates, gels, and precipitates in aqueous solutions [70][71][72]. One should note the recent paper by Du et al., which demonstrates that bile acids can aggregate at a concentration much lower than CMC, when specific conditions are created, such as the interactions with polyelectrolytes [76]
In experiments on model lipid membranes (black lipid membrane), it is well established that free (non-conjugated) bile acids—CA and DCA—are capable of transporting divalent metal ions (Ba2+, Ca2+, Sr2+, Mg2+, and Mn2+) [16].
Currently, several structures are known that transport Ca2+ in mitochondria. Among them, the most important are the mitochondrial Ca2+ uniporter (MCU), Ca2+/H+ antiporter (Letm1), Ca2+/Na+ antiporter (NCLX), and others [36][77]. The effect of bile acids as inducers of Ca2+ release from the matrix was studied in experiments on isolated rat liver mitochondria [43]. In these studies, mitochondria in the presence of cyclosporin A (a Ca2+-dependent pore blocker, see below) were fueled by succinate, loaded with Ca2+, and deenergized with malonate after addition of ruthenium red, a calcium uniporter inhibitor. It has been shown that under these conditions, bile acids—LCA, HDCA, CA, and UDCA—induce the release of Ca2+ from the mitochondrial matrix. The release of these ions was not associated with damage to the inner membrane of mitochondria by bile acids, as it is accompanied by the generation of Δψ—the formation of a diffusion potential. It was suggested that by ejecting Ca2+ from the matrix, bile acids transport H+ in the opposite direction, i.e., carry out electrically neutral Ca2+/2H+ exchange [43].
As noted above, bile acids are relatively flat and rigid molecules with a polar and a hydrophobic face [1][12][47][49]. A complex can be envisioned that would consist of two such molecules, with Ca2+ sequestered between the two hydrophilic surfaces [73]. It has been suggested that bile acids are likely to function as mobile (in contrast to channel-forming) Ca2+ ionophores, with the 2:1 bile acid/Ca2+ complex as the possible transport intermediate [18][73]. Based on the foregoing, the following hypothetical scheme can be assumed (Figure 2).
/media/item_content/202306/64814a2f8e19emembranes-13-00472-g003.png
Figure 2. Hypothetical scheme illustrating Ca2+ transport by bile acids directly across the phospholipid bilayer of the inner membrane of liver mitochondria. In this scheme, the first three stages are similar to the first three stages of proton transport by bile acids, as shown in Figure 1. Two bile acid anions (symbol 2(−)) are protonated on the outer surface of the inner membrane (step 1). Two neutral bile acid molecules (symbol 2(H)) are transported across the phospholipid bilayer to the opposite side of the membrane by the flip-flop mechanism (step 2). Two neutral bile acid molecules release two protons into the matrix (deprotonate) on the inner surface of the inner membrane to form two bile acid anions (step 3). These anions interact with Ca2+ to form an electrically neutral complex (symbol (−)(Ca2+)(−)) (step 4). This complex (a hypothetical structure is depicted on the right side [73]) moves through the phospholipid bilayer of the inner membrane to its outer surface (step 5), where this complex decomposes with the release of Ca2+ into the intermembrane space and the formation of two bile acid ions (step 6).

3.3. Bile Acids as Inducers of the Ca2+-Dependent Cyclosporine A-Sensitive Pore in the Inner Mitochondrial Membrane

As noted in the introduction, one of the links in cell death associated with mitochondria is the opening of a Ca2+-dependent MPT-pore in the inner membrane of these organelles for ions and hydrophilic substances, whose mass does not exceed 1.5 kDa along their concentration gradient. A highly selective inhibitor of this pore is cyclosporin A (CsA) which completely inhibits MPT-pore opening at submicromolar concentrations [32][33][34][35][36][37]. The opening of the MPT-pore promotes rapid transfer of protons into mitochondria leading to depolarization of the inner membrane, uncoupling of oxidative phosphorylation, and, simultaneously, rapid release of Ca2+ from the matrix. In this case, water with dissolved low molecular weight substances rushes into the mitochondria due to colloid osmotic pressure leading to high-amplitude swelling of the organelles. Swelling of mitochondria leads to a decrease in the light scattering through the suspension, and this can be registered as a decrease in the optical density of the mitochondrial suspension [78][79].
Thus, registration of a decrease in the optical density of a suspension of mitochondria associated with the swelling of these organelles is one of the main methods for determining the pore induction [38][42][43][44][78][79][80][81].
The process of closing–opening of the CsA-sensitive pore is regulated by a number of physiological modulators. Among low molecular weight pore modulators, inorganic phosphate (Pi) occupies a special place. It is well known that Pi increases the sensitivity of mitochondria to Ca2+ as a pore inductor. Pi has also been found to enhance the effect of CsA as a pore blocker [82][83][84][85][86].
It should be noted that a number of studies allows the consideration of the mitochondrial pore as a mechanism for the release of Ca2+ from organelles [87][88]. The question is being discussed of whether the non-selectivity of the mitochondrial pore is an important feature that allows the rapid and efficient release of Ca2+ from the matrix of organelles, which suggests the physiological role of this system (see reviews [36][89]).
LCA, DCA, HDCA, UDCA, as well as their glycine and taurine conjugates, are able to induce pore opening, which is inhibited by CsA in mitochondria isolated from the liver and loaded with Ca2+ [38][42][43][44][80][82][90]. In these experiments, the concentration of Ca2+ did not exceed 50 µM, and the concentration of bile acids was less than CMC by more than an order of magnitude (see Table 1). It is of note that the action of these bile acids as inducers of the mitochondrial CsA-sensitive pore is not associated with the modulation of the effect of inorganic phosphate as a pore inducer [42]. The effectiveness of bile acids as inducers of the Ca2+-dependent CsA-sensitive pore depends on the hydrophobicity of their molecules. The most hydrophobic LCA is the most effective, the less hydrophobic DCA and HDCA are less effective, and the more hydrophilic CA is significantly less effective [38][42]. At the same time, UDCA, being as hydrophobic as DCA and CDCA (Table 1), is significantly inferior to them in terms of efficiency as an inducer of the Ca2+-dependent CsA-sensitive pore [38][42]. Glycine and taurine conjugates of these bile acids are significantly less effective as inducers of the mitochondrial CsA-sensitive pore [38][82] despite their lower CMC (Table 1).
Table 1. Physico-chemical properties of the bile acids.
Bile Acid
(Trivial Name)		 Symbol Position and Orientation of Hydroxyls CMC (mM) logPHA logPA logP*
Water 0.15 M Na+
Cholic acid CA 3α7α12α 13 11 2.02 1.10 2.02
Taurocholic acid TCA 3α7α12α 10 6 - −0.50 0.66
Glycocholic acid GCA 3α7α12α 12 10 1.65 −0.40 1.65
Chenodeoxycholic acid CDCA 3α7α 9 4 3.28 2.25 3.08
Glycochenodeoxycholic acid GCDCA 3α7α 6 2 2.12 0.45 2.43
Ursodeoxycholic acid UDCA 3α7β 19 7 3.00 2.20 3.08
Glycoursodeoxycholic acid GUDCA 3α7β 12 4 2.02 0.20 2.43
Deoxycholic acid DCA 3α12α 10 3 3.50 2.65 3.50
Glycodeoxycholic acid GDCA 3α12α 6 2 2.25 0.80 2.25
Lithocholic acid LCA 3α 0.9 0.5 - - 4.42
CMC—critical micelle concentration [50]. logPHA—logarithm of the octanol/water partition coefficient at pH 2.0; logPA—logarithm of the octanol/water partition coefficient at pH 7.4 [51]. logP*—logarithm of the octanol/water partition coefficient theoretically calculated from the structural formulas of bile acids (Computed by XLogP3 (v3.2.2 [91]).
It was found that ruthenium red by inhibiting Ca2+ transport into the mitochondrial matrix is able to reduce the effect of bile acids as inducers of the CsA-sensitive mitochondrial pore [43]. Obviously, this is possible only if, as mentioned above, these bile acids are able to effectively induce the release of Ca2+ from the matrix without violating the integrity of the inner membrane, while ruthenium red prevents the return of these ions to the matrix. It is noted that other amphiphilic compounds do not have such an effect, in particular the free fatty acids: palmitic and α,ω-hexadecanedioic (Unpublished data of E. Khoroshavina). Thus, under conditions of reduced activity of the calcium uniporter, the release of Ca2+ from the matrix induced by bile acids may be one of the mechanisms that reduce the effectiveness of their action as inducers of the Ca2+-dependent CsA-sensitive pore in mitochondria.
Unlike other studied bile acids, the effects of UDCA associated with the induction of the permeability of the inner membrane (swelling of mitochondria, a drop in Δψ, and the release of Ca2+ from the matrix) in the presence of potassium chloride in the incubation medium, but without Pi, are also observed in the presence of CsA [42]. Obviously, these effects of UDCA, in contrast to the effects of other studied bile acids, are due to a different spatial orientation of the hydroxyl group at the seventh carbon atom of the steroid nucleus—the β-position instead of α-position, as in CDCA (Table 1). It suggests that the induction of CsA-insensitive inner membrane permeability by UDCA is associated with the activation of electrophoretic transport of K+ into the matrix of Ca2+-loaded mitochondria. This is known to be accompanied by their swelling and decrease in Δψ (see reviews [92][93]). Thus, UDCA can be considered as a K+ ionophore. At the same time, the involvement of other potassium ion transport systems, in particular Ca2+-activated K+ channels, cannot be ruled out [93].

References

  1. di Gregorio, M.C.; Cautela, J.; Galantini, L. Physiology and physical chemistry of bile acids. Int. J. Mol. Sci. 2021, 22, 1780.
  2. Shulpekova, Y.; Shirokova, E.; Zharkova, M.; Tkachenko, P.; Tikhonov, I.; Stepanov, A.; Sinitsyna, A.; Izotov, A.; Butkova, T.; Shulpekova, N.; et al. A recent ten-year perspective: Bile acid metabolism and signaling. Molecules 2022, 27, 1983.
  3. Begley, M.; Gahan, C.G.; Hill, C. The interaction between bacteria and bile. FEMS Microbiol. Rev. 2005, 29, 625–651.
  4. Urdaneta, V.; Casadesús, J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts. Front. Med. 2017, 4, 163.
  5. Zhou, H.; Hylemon, P.B. Bile acids are nutrient signaling hormones. Steroids 2014, 86, 62–68.
  6. Grant, S.M.; DeMorrow, S. Bile acid signaling in neurodegenerative and neurological disorders. Int. J. Mol. Sci. 2020, 21, 5982.
  7. Zagoskin, P.P.; Erlykina, E.I. Bile acids as a new type of steroid hormones regulating nonspecific energy expenditure of the body (Review). Sovrem. Tekhnologii Med. 2021, 12, 114–127.
  8. Way, G.W.; Jackson, K.G.; Muscu, S.R.; Zhou, H. Key signaling in alcohol-associated liver disease: The role of bile acids. Cells 2022, 11, 1374.
  9. Weng, Z.B.; Chen, Y.R.; Lv, J.T.; Wang, M.X.; Chen, Z.Y.; Zhou, W.; Shen, X.C.; Zhan, L.B.; Wang, F. A review of bile acid metabolism and signaling in cognitive dysfunction-related diseases. Oxid. Med. Cell. Longev. 2022, 2022, 4289383.
  10. Schölmerich, J.; Becher, M.S.; Schmidt, K.; Schubert, R.; Kremer, B.; Feldhaus, S.; Gerok, W. Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties—Studies on isolated hepatocytes and lipid membrane vesicles. Hepatology 1984, 4, 661–666.
  11. O’Connor, C.J.; Wallace, R.G.; Iwamoto, K.; Taguchi, T.; Sunamoto, J. Bile salt damage of egg phosphatidyl choline liposomes. Biochim. Biophys. Acta 1985, 817, 95–102.
  12. Garidel, P.; Hildebrand, A.; Knauf, K.; Blume, A. Membranolytic activity of bile salts: Influence of biological membrane properties and composition. Molecules 2007, 12, 2292–2326.
  13. Camilleri, M. Bile acid detergency: Permeability, inflammation, and effects of sulfation. Am. J. Physiol. Gastrointest. Liver Physiol. 2022, 322, 480–488.
  14. Zhao, D.; Hirst, B.H. Prostaglandin protects against bile salt induced increases in proton permeation of duodenal brush border membrane. Gut. 1991, 32, 645–648.
  15. Kamp, F.; Hamilton, J.A. Movement of fatty acids, fatty acid analogues, and bile acids across phospholipid bilayers. Biochemistry 1993, 32, 11074–11086.
  16. Abramson, J.J.; Shamoo, A.E. Anionic detergents as divalent cation ionophores across black lipid membranes. J. Membr. Biol. 1979, 50, 241–455.
  17. Hunt, G.R.; Jawaharlal, K. A 1H-NMR investigation of the mechanism for the ionophore activity of the bile salts in phospholipid vesicular membranes and the effect of cholesterol. Biochim. Biophys. Acta 1980, 601, 678–684.
  18. Oelberg, D.G.; Wang, L.B.; Sackman, J.W.; Adcock, E.W.; Lester, R.; Dubinsky, W.P. Bile salt-induced calcium fluxes in artificial phospholipid vesicles. Biochim. Biophys. Acta 1988, 937, 289–299.
  19. Arduini, A.; Serviddio, G.; Escobar, J.; Tormos, A.M.; Bellanti, F.; Vina, J.; Monsalve, M.; Sastre, J. Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 301, 119–127.
  20. Arduini, A.; Serviddio, G.; Tormos, A.M.; Monsalve, M.; Sastre, J. Mitochondrial dysfunction in cholestatic liver diseases. Front. Biosci. 2012, 4, 2233–2252.
  21. Monte, M.J.; Marin, J.J.; Antelo, A.; Vazquez-Tato, J. Bile acids: Chemistry, physiology, and pathophysiology. World J. Gastroenterol. 2009, 15, 804–816.
  22. Combettes, L.; Dumont, M.; Berthon, B.; Erlinger, S.; Claret, M. Release of calcium from the endoplasmic reticulum by bile acids in rat liver cells. J. Biol. Chem. 1988, 26, 2299–2303.
  23. Goldberg, A.A.; Beach, A.; Davies, G.F.; Harkness, T.A.; Leblanc, A.; Titorenko, V.I. Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget 2011, 10, 761–782.
  24. Malhi, H.; Guicciardi, M.E.; Gores, G.L. Hepatocyte death: A clear and present danger. Physiol. Rev. 2010, 90, 165–1194.
  25. Woolbright, B.L.; Li, F.; Xie, Y.; Farhood, A.; Fickert, P.; Trauner, M.; Jaeschke, H. Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice. Toxicol. Lett. 2014, 228, 56–66.
  26. Luu, T.H.; Bard, J.M.; Carbonnelle, D.; Chaillou, C.; Huvelin, J.M.; Bobin-Dubigeon, C.; Nazih, H. Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells. Cell. Oncol. 2018, 41, 13–24.
  27. Guarino, M.P.; Cocca, S.; Altomare, A.; Emerenziani, S.; Cicala, M. Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World J. Gastroenterol. 2013, 19, 5029–5034.
  28. Keely, S.J.; Steer, C.J.; Lajczak-McGinley, N.K. Ursodeoxycholic acid: A promising therapeutic target for inflammatory bowel diseases? Am. J. Physiol. Gastrointest. Liver Physiol. 2019, 317, 872–881.
  29. Daruich, A.; Picard, E.; Guégan, J.; Jaworski, T.; Parenti, L.; Delaunay, K.; Naud, M.C.; Berdugo, M.; Boatright, J.H.; Behar-Cohen, F. Comparative analysis of urso-and tauroursodeoxycholic acid neuroprotective effects on retinal degeneration models. Pharmaceuticals 2022, 15, 334.
  30. Lee, J.; Giordano, S.; Zhang, J. Autophagy, mitochondria and oxidative stress: Cross-talk and redox signalling. Biochem. J. 2012, 441, 523–540.
  31. Bauer, T.M.; Murphy, E. Role of mitochondrial calcium and the permeability transition pore in regulating cell death. Circ. Res. 2020, 126, 280–293.
  32. Bonora, M.; Patergnani, S.; Ramaccini, D.; Morciano, G.; Pedriali, G.; Kahsay, A.E.; Bouhamida, E.; Giorgi, C.; Wieckowski, M.R.; Pinton, P. Physiopathology of the permeability transition pore: Molecular mechanisms in human pathology. Biomolecules 2020, 10, 998.
  33. Bonora, M.; Giorgi, C.; Pinton, P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat. Rev. Mol. Cell. Biol. 2022, 23, 266–285.
  34. Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 2014, 94, 909–950.
  35. Belosludtsev, K.N.; Belosludtseva, N.V.; Dubinin, M.V. Diabetes mellitus, mitochondrial dysfunction and Ca2+-dependent permeability transition pore. Int. J. Mol. Sci. 2020, 21, 6559.
  36. Belosludtsev, K.N.; Dubinin, M.V.; Belosludtseva, N.V.; Mironova, G.D. Mitochondrial Ca2+ transport: Mechanisms, molecular structures, and role in cells. Biochemistry 2019, 84, 593–607.
  37. Bernardi, P.; Carraro, M.; Lippe, G. The mitochondrial permeability transition: Recent progress and open questions. FEBS J. 2022, 289, 7051–7074.
  38. Rolo, A.P.; Oliveira, P.J.; Moreno, A.J.; Palmeira, C.M. Bile acids affect liver mitochondrial bioenergetics: Possible relevance for cholestasis therapy. Toxicol. Sci. 2000, 57, 177–185.
  39. Ferreira, M.; Coxito, P.M.; Sardão, V.A.; Palmeira, C.M.; Oliveira, P.J. Bile acids are toxic for isolated cardiac mitochondria: A possible cause for hepatic-derived cardiomyopathies? Cardiovasc. Toxicol. 2005, 5, 63–73.
  40. Sousa, T.; Castro, R.E.; Pinto, S.N.; Coutinho, A.; Lucas, S.D.; Moreira, R.; Rodrigues, C.M.P.; Prieto, M.; Fernandes, F. Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties. J. Lipid. Res. 2015, 56, 2158–2171.
  41. Khoroshavina, E.I.; Dubinin, M.V.; Samartsev, V.N. The effects of bile acids on the liver mitochondria in the presence and absence of Ca2+. FEBS J. 2015, 282 (Suppl. S1), 100.
  42. Khoroshavina, E.I.; Dubinin, M.V.; Samartsev, V.N. 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. Biochem. Mosc. Suppl. Ser. A 2016, 10, 287–293.
  43. Khoroshavina, E.I.; Dubinin, M.V.; Khokhlov, A.V.; Samartsev, V.N. Bile acid-induced Ca2+ efflux from liver mitochondria as a factor preventing the formation of mitochondrial pores. Biochem. Mosc. Suppl. Ser. A 2018, 12, 128–136.
  44. Dubinin, M.V.; Khoroshavina, E.I.; Samartsev, V.N. Lithocholic acid induces two different calcium-dependent inner membrane permeability systems in liver mitochondria. Biochem. Mosc. Suppl. Ser. A 2017, 11, 231–236.
  45. Penman, S.L.; Sharma, P.; Aerts, H.; Park, B.K.; Weaver, R.J.; Chadwick, A.E. Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells. Toxicol. Vitr. 2019, 61, 104595.
  46. Abrigo, J.; Olguín, H.; Gutierrez, D.; Tacchi, F.; Arrese, M.; Cabrera, D.; Valero-Breton, M.; Elorza, A.A.; Simon, F.; Cabello-Verrugio, C. Bile acids induce alterations in mitochondrial function in skeletal muscle fibers. Antioxidants 2022, 11, 1706.
  47. Moghimipour, E.; Ameri, A.; Handali, S. Absorption-enhancing effects of bile salts. Molecules 2015, 20, 14451–14473.
  48. Mukhopadhyay, S.; Maitra, U. Chemistry and biology of bile acids. Curr. Sci. 2004, 87, 1666–1683.
  49. Madenci, D.; Egelhaaf, S.U. Self-assembly in aqueous bile salt solutions. Curr. Opin. Colloid. Interface Sci. 2010, 15, 109–115.
  50. Hofmann, A.F.; Roda, A. Physicochemical properties of bile acids and their relationship to biological properties: An overview of the problem. J. Lipid. Res. 1984, 25, 1477–1489.
  51. Roda, A.; Minutello, A.; Angellotti, M.A.; Fini, A. Bile acid structure-activity relationship: Evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. J. Lipid. Res. 1990, 31, 1433–1443.
  52. Chen, M.; Grätzel, M.; Thomas, J.K. Kinetic studies in bile acid micelles. J. Am. Chem. Soc. 1975, 97, 2052–2057.
  53. Terada, H. Uncouplers of oxidative phosphorylation. Environ. Health Perspect. 1990, 87, 213–218.
  54. Goedeke, L.; Shulman, G.I. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH. Mol. Metab. 2021, 46, 101178.
  55. Shrestha, R.; Johnson, E.; Byrne, F.L. Exploring the therapeutic potential of mitochondrial uncouplers in cancer. Mol. Metab. 2021, 46, 101222.
  56. Kotova, E.A.; Antonenko, Y.N. Fifty Years of research on protonophores: Mitochondrial uncoupling as a basis for therapeutic action. Acta Nat. 2022, 14, 4–13.
  57. Skulachev, V.P. Uncoupling: New approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1998, 1363, 100–124.
  58. Samartsev, V.N.; Semenova, A.A.; Dubinin, M.V. A comparative study of the action of protonophoreuncouplers and decoupling agents as inducers of free respiration in mitochondria in states 3 and 4: Theoretical and Experimental Approaches. Cell Biochem. Biophys. 2020, 78, 203–216.
  59. Semenova, A.A.; Samartsev, V.N.; Pavlova, S.I.; Dubinin, M.V. ω-Hydroxypalmitic and α,ω-hexadecanedioic acids as activators of free respiration and inhibitors of H2O2 generation in liver mitochondria. Biochem. Mosc. Suppl. Ser. A 2020, 14, 24–33.
  60. Zorov, D.B.; Andrianova, N.V.; Babenko, V.A.; Pevzner, I.B.; Popkov, V.A.; Zorov, S.D.; Zorova, L.D.; Plotnikov, E.Y.; Sukhikh, G.T.; Silachev, D.N. Neuroprotective potential of mild uncoupling in mitochondria. Pros and cons. Brain Sci. 2021, 11, 1050.
  61. Geisler, J.G. 2,4-Dinitrophenol as medicine. Cells 2019, 8, 280.
  62. Severin, F.F.; Severina, I.I.; Antonenko, Y.N.; Rokitskaya, T.I.; Cherepanov, D.A.; Mokhova, E.N.; Vyssokikh, M.Y.; Pustovidko, A.V.; Markova, O.V.; Yaguzhinsky, L.S.; et al. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc. Natl. Acad. Sci. USA 2010, 107, 663–668.
  63. Samartsev, V.N.; Marchik, E.I.; Shamagulova, L.V. Free fatty acids as inducers and regulators of uncoupling of oxidative phosphorylation in liver mitochondria with participation of ADP/ATP and aspartate/glutamate antiporter. Biochemistry 2011, 76, 217–224.
  64. Bertholet, A.M.; Chouchani, E.T.; Kazak, L.; Angelin, A.; Fedorenko, A.; Long, J.Z.; Vidoni, S.; Garrity, R.; Cho, J.; Terada, N.; et al. H+ transport is an integral function of the mitochondrial ADP/ATP carrier. Nature 2019, 7766, 515–520.
  65. Andreyev, A.Y.; Bondareva, T.O.; Dedukhova, V.I.; Mokhova, E.N.; Skulachev, V.P.; Tsofina, L.M.; Volkov, N.I.; Vygodina, T.V. The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. Eur. J. Biochem. 1989, 182, 585–592.
  66. Schönfeld, P. Does the function of adenine nucleotide translocase in fatty acid uncoupling depend on the type mitochondria? FEBS Lett. 1990, 264, 246–248.
  67. Samartsev, V.N.; Smirnov, A.V.; Zeldi, I.P.; Markova, O.V.; Mokhova, E.N.; Skulachev, V.P. Involved of aspartate/glutamate antiporter in fatty acid-induced uncoupling of liver mitochondria. Biochim. Biophys. Acta 1997, 1339, 251–257.
  68. Brustovetsky, N.N.; Dedukhova, V.I.; Egorova, M.V.; Mokhova, E.N.; Skulachev, V.P. Inhibitors of the ATP/ADP antiporter suppress stimulation of mitochondrial respiration and H+ permeability by palmitate and anionic detergents. FEBS Lett. 1990, 272, 187–189.
  69. Neves, M.C.; Filipe, H.A.L.; Reis, R.L.; Prates Ramalho, J.P.; Coreta-Gomes, F.; Moreno, M.J.; Loura, L.M.S. Interaction of bile salts with lipid bilayers: An atomistic molecular dynamics study. Front. Physiol. 2019, 10, 393.
  70. Gu, J.J.; Hofmann, A.F.; Ton-Nu, H.T.; Schteingart, C.D.; Mysels, K.J. Solubility of calcium salts of unconjugated and conjugated natural bile acids. J. Lipid. Res. 1992, 33, 635–646.
  71. D’Archivio, A.A.; Galantini, L.; Gavuzzo, E.; Giglio, E.; Mazza, F. Calcium ion binding to bile salts. Langmuir 1997, 13, 3090–3095.
  72. Hofmann, A.F.; Mysels, K.J. Bile acid solubility and precipitation in vitro and in vivo: The role of conjugation, pH, and Ca2+ ions. J. Lipid Res. 1992, 33, 617–626.
  73. Zimniak, P.; Little, J.M.; Radominska, A.; Oelberg, D.G.; Anwer, M.S.; Lester, R. Taurine-conjugated bile acids act as Ca2+ ionophores. Biochemistry 1991, 30, 8598–8604.
  74. Donovan, J.M.; Leonard, M.R.; Batta, A.K.; Carey, M.C. Calcium affinity for biliary lipid aggregates in model biles: Complementary importance of bile salts and lecithin. Gastroenterology 1994, 107, 831–846.
  75. Oelberg, D.G.; Dubinsky, W.P.; Adcock, E.W.; Lester, R. Calcium binding by lithocholic acid derivatives. Am. J. Physiol. 1984, 247 Pt 1, G112–G115.
  76. Du, G.; Belić, D.; Del Giudice, A.; Alfredsson, V.; Carnerup, A.M.; Zhu, K.; Nyström, B.; Wang, Y.; Galantini, L.; Schillén, K. Condensed supramolecular helices: The twisted sisters of DNA. Angew. Chem. Int. Ed. 2022, 61, e202113279.
  77. De Stefani, D.; Rizzuto, R.; Pozzan, T. Enjoy the trip: Calcium in mitochondria back and forth. Annu. Rev. Biochem. 2016, 85, 161–192.
  78. Petronilli, V.; Cola, C.; Massari, S.; Colonna, R.; Bernardi, P. Physiological effectors modify voltage sensing by the cyclosporin A-sensitive permeability transition pore of mitochondria. J. Biol. Chem. 1993, 268, 21939–21945.
  79. Sultan, A.; Sokolove, P. Palmitic acid opens anovel cyclosporin A-insensitive pore in the inner mitochondrial membrane. Arch. Biochem. Biophys. 2001, 386, 31–51.
  80. Schulz, S.; Schmitt, S.; Wimmer, R.; Aichler, M.; Eisenhofer, S.; Lichtmannegger, J.; Eberhagen, C.; Artmann, R.; Tookos, F.; Walch, A.; et al. Progressive stages of mitochondrial destruction caused by cell toxic bile salts. Biochim. Biophys. Acta 2013, 1828, 2121–2133.
  81. Mironova, G.D.; Belosludtsev, K.N.; Belosludtseva, N.V.; Gritsenko, E.N.; Khodorov, B.I.; Saris, N.E. Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporine A-insensitive pore. J. Bioenerg. Biomembr. 2007, 39, 167–174.
  82. Rolo, A.P.; Oliveira, P.J.; Moreno, A.J.; Palmeira, C.M. Chenodeoxycholate induction of mitochondrial permeability transition pore is associated with increased membrane fluidity and cytochrome c release: Protective role of carvedilol. Mitochondrion 2003, 2, 305–311.
  83. Chavez, E.; Moreno-Sanchez, R.; Zazueta, C.; Rodriguez, J.S.; Bravo, C.; Reyes-Vivas, H. On the protection by inorganic phosphate of calcium-induced membrane permeability transition. J. Bioenerg. Biomembr. 1997, 29, 571–577.
  84. Basso, E.; Petronilli, V.; Forte, M.A.; Bernardi, P. Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. J. Biol. Chem. 2008, 283, 26307–26311.
  85. McGee, A.M.; Baines, C.P. Phosphate is not an absolute requirement for the inhibitory effects of cyclosporine A or cyclophilin D deletion on mitochondrial permeability transition. J. Biochem. 2012, 443, 185–191.
  86. Dubinin, M.V.; Samartsev, V.N.; Starinets, V.S.; Khoroshavina, E.I.; Belosludtsev, K.N. 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. Biochem. Mosc. Suppl. Ser. A 2019, 13, 58–66.
  87. Elrod, J.W.; Wong, R.; Mishra, S.; Vagnozzi, R.J.; Sakthievel, B.; Goonasekera, S.A.; Karch, J.; Gabel, S.; Farber, J.; Force, T.; et al. Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice. J. Clin. Investig. 2010, 120, 3680–3687.
  88. Barsukova, A.; Komarov, A.; Hajnoczky, G.; Bernardi, P.; Bourdette, D.; Forte, M. Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. Eur. J. Neurosci. 2011, 33, 831–842.
  89. Mironova, G.D.; Pavlov, E.V. 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 2021, 10, 125.
  90. Gores, G.J.; Miyoshi, H.; Botla, R.; Aguilar, H.I.; Bronk, S.F. Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: A potential role for mitochondrial proteases. Biochim. Biophys. Acta 1998, 1366, 167–175.
  91. Cheng, T.; Zhao, Y.; Li, X.; Lin, F.; Xu, Y.; Zhang, X.; Li, Y.; Wang, R.; Lai, L. Computation of octanol-water partition coefficients by guiding an additive model with knowledge. J. Chem. Inf. Model. 2007, 47, 2140–2148.
  92. Bernardi, P. Mitochondrial transport of cations: Channels, exchengers, and permeability transition. Physiol. Rev. 1999, 79, 1127–1155.
  93. Szabo, I.; Zoratti, M. Mitochondrial channels: Ion fluxes and more. Physiol. Rev. 2014, 94, 519–608.
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Subjects: Biophysics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Victor N. Samartsev
,
Ekaterina I. Khoroshavina
,
Evgeniya K. Pavlova
,
Mikhail V. Dubinin
,
Alena A. Semenova
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Revisions: 2 times (View History)
Update Date: 08 Jun 2023
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