The ionization properties of cardiolipin and its variants in model bilayers

Sathappa, Murugappan; Alder, Nathan N.

doi:10.1016/j.bbamem.2016.03.007

Cited by 84 publications

(97 citation statements)

References 88 publications

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“…This is the reason for extensive research that has revisited the initial, early, observations of the pKa(s) of CL over the last two decades. The latest published findings concluded that both phosphates of CL dispersions in water are strong dibasic acids similar to phosphoric acid (pKa ~2) [12], and recent zeta potential measurements also concluded that CL has only one pKa [13]. These results are all indirect measures of the charge on the entire membrane surface.…”

Section: Discussionmentioning

confidence: 99%

“…The difference between the pKa values of the two phosphate groups in aqueous dispersions of CL was found to be small and of the order of one pH unit [12]. Another recent study used electrophoretic measurements to show that the charge on CL at neutral pH is most likely −2 [13]. These studies were performed on pure CL (Olofsson and Sparr [12]), and/or did not take into account the phase behavior of CL [13] which can change from bilayer to inverted hexagonal phase (H II ) as a function of pH, where at low pH the H II phase dominates.…”

Section: Introductionmentioning

confidence: 99%

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Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes

Kooijman¹,

Swim²,

Graber³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Specific membrane lipid composition is crucial for optimized structural and functional organization of biological membranes. Cardiolipin is a unique phospholipid and important component of the inner mitochondrial membrane. It is involved in energy metabolism, inner mitochondrial membrane transport, regulation of multiple metabolic reactions and apoptotic cell death. The physico-chemical properties of cardiolipin have been studied extensively but despite all these efforts there is still lingering controversy regarding the ionization of the two phosphate groups of cardiolipin. Results obtained in the 1990s and early 2000s suggested that cardiolipin has two disparate pKa values where one of the protons was proposed to be stabilized by an intramolecular hydrogen bond. This has led to extensive speculations on the roles of these two putative ionization states of cardiolipin in mitochondria. More recently the notion of two pKa values has been challenged and rejected by several groups. These studies relied on external measurements of proton adsorption or electrophoretic mobility of membranes but did not take into account the low pH phase behavior and chemical stability of cardiolipin. Here we used 31P NMR to show that in the physiologically relevant membrane phospholipid environment, cardiolipin carries two negative charges at physiological pH. We additionally demonstrate the pH dependent phase behavior and chemical stability of cardiolipin containing membranes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes

Kooijman¹,

Swim²,

Graber³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…While the pKa of the phosphates of CL had originally been described as strong acids and were doubly negatively charged [53], a pH titration study comparing a native and 2'-deoxy-glycerol backbone suggested that there was both a low and high pKa[54]. Subsequently membrane measurements of CL using external proton adsorption, electrophoretic mobility of membranes and magic angle spinning P 31 NMR have clearly shown that the pKa of CL as well as lyso-CL is ~2-3 indicating that both phosphates are ionized at physiological pH in lipid bilayers [55-57]. Thus it seems logical or almost certain that at physiological pH, CLs in lipid bilayers adopt the states with two fully ionized phosphate groups.…”

Section: Cardiolipin Its Molecular Structure Homo- and Hetero-acylamentioning

confidence: 99%

Known unknowns of cardiolipin signaling: The best is yet to come

Maguire

Tyurina

Mohammadyani

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

103

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Since its discovery 75 years ago, a wealth of knowledge has accumulated on the role of cardiolipin, the hallmark phospholipid of mitochondria, in bioenergetics and particularly on the structural organization of the inner mitochondrial membrane. A surge of interest in this anionic doubly-charged tetra-acylated lipid found in both prokaryotes and mitochondria has emerged based on its newly discovered signaling functions. Cardiolipin displays organ, tissue, cellular and transmembrane distribution asymmetries. A collapse of the membrane asymmetry represents a pro-mitophageal mechanism whereby externalized cardiolipin acts as an “eat-me” signal. Oxidation of cardiolipin's polyunsaturated acyl chains - catalyzed by cardiolipin complexes with cytochrome c. - is a pro-apoptotic signal. The messaging functions of myriads of cardiolipin species and their oxidation products are now being recognized as important intracellular and extracellular signals for innate and adaptive immune systems. This newly developing field of research exploring cardiolipin signaling is the main subject of this review.

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“…It has been proposed that under physiological conditions, the central hydroxyl and the two phosphates trap a proton in a resonance structure and that cardiolipin carries one net negative charge (5). However, re-evaluations of the pK a values of the phosphates indicate that under physiological conditions, the head-group of cardiolipin bears two negative charges (6,7).…”

mentioning

confidence: 99%

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

Duncan

Robinson

Walker

2016

Proc. Natl. Acad. Sci. U.S.A.

128

132

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The anionic lipid cardiolipin is an essential component of active ATP synthases. In metazoans, their rotors contain a ring of eight c-subunits consisting of inner and outer circles of N-and C-terminal α-helices, respectively. The beginning of the C-terminal α-helix contains a strictly conserved and fully trimethylated lysine residue in the lipid headgroup region of the membrane. Larger rings of known structure, from c 9 -c 15 in eubacteria and chloroplasts, conserve either a lysine or an arginine residue in the equivalent position. In computer simulations of hydrated membranes containing trimethylated or unmethylated bovine c 8 -rings and bacterial c 10 -or c 11 -rings, the head-groups of cardiolipin molecules became associated selectively with these modified and unmodified lysine residues and with adjacent polar amino acids and with a second conserved lysine on the opposite side of the membrane, whereas phosphatidyl lipids were attracted little to these sites. However, the residence times of cardiolipin molecules with the ring were brief and sufficient for the rotor to turn only a fraction of a degree in the active enzyme. With the demethylated c 8 -ring and with c 10 -and c 11 -rings, the density of bound cardiolipin molecules at this site increased, but residence times were not changed greatly. These highly specific but brief interactions with the rotating c-ring are consistent with functional roles for cardiolipin in stabilizing and lubricating the rotor, and, by interacting with the enzyme at the inlet and exit of the transmembrane proton channel, in participation in proton translocation through the membrane domain of the enzyme.ardiolipin is associated uniquely with energy-transducing membranes in mitochondria and eubacteria. In mitochondria, it is found in the inner membrane and is synthesized close to, or in, the inner leaflet (1) where most of it remains (2, 3). Cardiolipin consists of two 3-phosphatidyl groups linked by a glycerol bridge, and in bovine mitochondria, the four acyl chains have 18 carbon atoms with one or two unsaturated linkages (4). It has been proposed that under physiological conditions, the central hydroxyl and the two phosphates trap a proton in a resonance structure and that cardiolipin carries one net negative charge (5). However, re-evaluations of the pK a values of the phosphates indicate that under physiological conditions, the head-group of cardiolipin bears two negative charges (6, 7).Cardiolipin and other phospholipids are essential components of active ATP synthases isolated from mitochondria (8-12). It has been suggested that cardiolipin acts to stabilize and lubricate the rotating c-ring (13) or to aid in proton transfer (5), but it is not known where or how cardiolipin binds to the enzyme. Excluding the regulatory protein IF 1, the bovine ATP synthase complex is built from 28 polypeptide chains of 16 varieties (14). About 85% of a mosaic overall structure has been determined to atomic resolution by structural analysis of constituent domains (15-18), and an intact enzyme ...

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The ionization properties of cardiolipin and its variants in model bilayers

Cited by 84 publications

References 88 publications

Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes

Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes

Known unknowns of cardiolipin signaling: The best is yet to come

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

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