Cardiolipin in Immune Signaling and Cell Death
2020; Elsevier BV; Volume: 30; Issue: 11 Linguagem: Inglês
10.1016/j.tcb.2020.09.004
ISSN1879-3088
AutoresMalvina Pizzuto, Pablo Pelegrı́n,
Tópico(s)Neutrophil, Myeloperoxidase and Oxidative Mechanisms
ResumoProapoptotic or pathogen signals induce translocation of cardiolipin (CL) from the inner to the outer mitochondrial membrane (OMM).Exposed CL mediates degradation of damaged intracellular mitochondria and phagocytosis of mitochondria from the extracellular milieu.Exposed CL in mitochondria acts as a platform for inflammasome localization and activation.Oxidation of CL and exposure on the OMM induce cytochrome c release and apoptosis.Exogenous uCL inhibits lipopolysaccharide (LPS)-induced proinflammatory signaling via TLR4, whereas saturated CL mimics bacterial LPS and activates TLR4. Cardiolipin (CL) is a tetra-acylated diphosphatidylglycerol lipid. In physiological conditions, CL presents unsaturated chains and is located in the inner mitochondria membrane (IMM). Dead signals, infection, or disease may change the level of CL saturation and oxidation and cause its translocation to the cytosolic side of the outer mitochondrial membrane (OMM), affecting mitochondrial function and the inflammatory response. In this review, we summarize the emerging proapoptotic, pro-, and anti-inflammatory functions of cytosolic-exposed CL and how they are regulated by CL chain saturation and oxidation. We underline how the unique dimeric phospholipid structure confers peculiar properties on CL in the regulation of cell death and immune system proteins, such as the Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3), caspases (Casp), and Toll-like receptor 4 (TLR4). We also provide an overview of the human diseases in which CL deficiency or modification are implicated and of the use of exogenous unsaturated CL (uCL) as a novel therapeutic approach. Cardiolipin (CL) is a tetra-acylated diphosphatidylglycerol lipid. In physiological conditions, CL presents unsaturated chains and is located in the inner mitochondria membrane (IMM). Dead signals, infection, or disease may change the level of CL saturation and oxidation and cause its translocation to the cytosolic side of the outer mitochondrial membrane (OMM), affecting mitochondrial function and the inflammatory response. In this review, we summarize the emerging proapoptotic, pro-, and anti-inflammatory functions of cytosolic-exposed CL and how they are regulated by CL chain saturation and oxidation. We underline how the unique dimeric phospholipid structure confers peculiar properties on CL in the regulation of cell death and immune system proteins, such as the Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3), caspases (Casp), and Toll-like receptor 4 (TLR4). We also provide an overview of the human diseases in which CL deficiency or modification are implicated and of the use of exogenous unsaturated CL (uCL) as a novel therapeutic approach. CL is a tetra-acylated diphosphatidylglycerol lipid found in bacteria, yeast, plants, and animals. Acyl chain length and degree of unsaturation vary depending on species, tissue, and pathological conditions [1.Oemer G. et al.Molecular structural diversity of mitochondrial cardiolipins.Proc. Natl. Acad. Sci. 2018; 115: 4158-4163Crossref PubMed Scopus (59) Google Scholar]. In mammals, CL is synthesized on the matrix side of the IMM by the enzyme CL synthase (CLS) through condensation of phosphatidylglycerol phosphate (PGP) and cytidine diphosphate diacylglycerol (CDP-DAG) [2.Lu Y.-W. Claypool S.M. Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes.Front. Genet. 2015; 6: 1-27Crossref PubMed Scopus (96) Google Scholar] (Figure 1A ). This produces immature CL with a highly heterogeneous and asymmetric fatty acid composition. In the outer leaflet of the IMM, specific unsaturated fatty acids are added through massive cell- and tissue-dependent enzymatic remodeling mediated by Tafazzin (TAZ) (Figure 1A), a transacylase protein named after a comic Italian character [3.Schlame M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes.J. Lipid Res. 2008; 4: 1607-1620Crossref Scopus (294) Google Scholar]. Mutations of TAZ result in a decrease in uCL, and accumulation of saturated CL (sCL) and monolyso (see Glossary)-CL (MLCL) (Figure 1B) and are causative of the rare condition 'Barth syndrome'. Under physiological conditions, CL is absent in the OMM and is found in a similar amount in the inner and outer leaflet of the IMM [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar]. However, the concentration of uCL is probably higher in the outer leaflet of IMM, where TAZ mediates CL remodeling from immature to unsaturated forms [3.Schlame M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes.J. Lipid Res. 2008; 4: 1607-1620Crossref Scopus (294) Google Scholar] (Figure 2A ). Moreover, because of its conical shape, CL is unevenly distributed along the leaflets, concentrating on concave surfaces. Hence, in the cristae of the IMM, CL is present in the outer leaflet, facing the intermembrane space, where it performs important functions in energy metabolism (Box 1) [5.Szeto H.H. Liu S. Cardiolipin-targeted peptides rejuvenate mitochondrial function, remodel mitochondria, and promote tissue regeneration during aging.Arch. Biochem. Biophys. 2018; 660: 137-148Crossref PubMed Scopus (44) Google Scholar,6.Ikon N. Ryan R.O. Cardiolipin and mitochondrial cristae organization.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1156-1163Crossref PubMed Scopus (156) Google Scholar]. The conical shape of CL also favors mitochondrial membrane fusion and fission, which are likely regulated by an asymmetric distribution of CL [2.Lu Y.-W. Claypool S.M. Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes.Front. Genet. 2015; 6: 1-27Crossref PubMed Scopus (96) Google Scholar].Box 1Role of Cardiolipin in Respiratory FunctionsCL is asymmetrically distributed in the mitochondrial membrane, where, due to its peculiar conical shape and dimeric nature, it contributes to bioenergetics processes crucial for cell life. Its conical shape causes the enrichment of CL into the negatively curved monolayer of the IMM, stabilizing membrane curvature and permitting the formation of mitochondrial cristae [6.Ikon N. Ryan R.O. Cardiolipin and mitochondrial cristae organization.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1156-1163Crossref PubMed Scopus (156) Google Scholar], the characteristic tube-like inward folds of the IMM. Cristae morphology is important for the oxidative phosphorylation system (OXPHOS). OXPHOS is the process by which cell energy is produced in the form of ATP using the proton gradient created by the electron transport chain (ETC) [62.Quintana-Cabrera R. et al.Who and how in the regulation of mitochondrial cristae shape and function.Biochem. Biophys. Res. Commun. 2018; 500: 94-101Crossref PubMed Scopus (70) Google Scholar]. CL is vital to OXPHOS, not only because it permits cristae formation, but also because it binds and stabilizes all enzymes of the ETC and is required for the activity of complex I, III, IV, and ATP synthase [63.Musatov A. Sedlák E. Role of cardiolipin in stability of integral membrane proteins.Biochimie. 2017; 142: 102-111Crossref PubMed Scopus (48) Google Scholar]. Interestingly, CL oxidation decreases the efficiency of complex I, II, and IV, which can be restored by adding uCL liposomes [64.Paradies G. et al.Role of cardiolipin in mitochondrial function and dynamics in health and disease: molecular and pharmacological aspects.Cells. 2019; 8: 728Crossref Scopus (150) Google Scholar]. CL also increases the respiratory efficiency by contributing to the highly ordered organization of complex I, III, and IV in supercomplexes [65.Mileykovskaya E. Dowhan W. Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes.Chem. Phys. Lipids. 2014; 179: 42-48Crossref PubMed Scopus (175) Google Scholar]. Moreover, CL is required for the activity of ADP and Pi carriers, supplying substrate for ATP production [66.Claypool S.M. Cardiolipin, a critical determinant of mitochondrial carrier protein assembly and function.Biochim. Biophys. Acta Biomembr. 2009; 1788: 2059-2068Crossref PubMed Scopus (152) Google Scholar]. Finally, due to its dimeric polar head, CL acts as a proton trap supplying protons to ATP synthase while minimizing pH changes in the intermembrane space [67.Haines T.H. Dencher N.A. Cardiolipin: a proton trap for oxidative phosphorylation.FEBS Lett. 2002; 528: 35-39Crossref PubMed Scopus (316) Google Scholar]. CL is asymmetrically distributed in the mitochondrial membrane, where, due to its peculiar conical shape and dimeric nature, it contributes to bioenergetics processes crucial for cell life. Its conical shape causes the enrichment of CL into the negatively curved monolayer of the IMM, stabilizing membrane curvature and permitting the formation of mitochondrial cristae [6.Ikon N. Ryan R.O. Cardiolipin and mitochondrial cristae organization.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1156-1163Crossref PubMed Scopus (156) Google Scholar], the characteristic tube-like inward folds of the IMM. Cristae morphology is important for the oxidative phosphorylation system (OXPHOS). OXPHOS is the process by which cell energy is produced in the form of ATP using the proton gradient created by the electron transport chain (ETC) [62.Quintana-Cabrera R. et al.Who and how in the regulation of mitochondrial cristae shape and function.Biochem. Biophys. Res. Commun. 2018; 500: 94-101Crossref PubMed Scopus (70) Google Scholar]. CL is vital to OXPHOS, not only because it permits cristae formation, but also because it binds and stabilizes all enzymes of the ETC and is required for the activity of complex I, III, IV, and ATP synthase [63.Musatov A. Sedlák E. Role of cardiolipin in stability of integral membrane proteins.Biochimie. 2017; 142: 102-111Crossref PubMed Scopus (48) Google Scholar]. Interestingly, CL oxidation decreases the efficiency of complex I, II, and IV, which can be restored by adding uCL liposomes [64.Paradies G. et al.Role of cardiolipin in mitochondrial function and dynamics in health and disease: molecular and pharmacological aspects.Cells. 2019; 8: 728Crossref Scopus (150) Google Scholar]. CL also increases the respiratory efficiency by contributing to the highly ordered organization of complex I, III, and IV in supercomplexes [65.Mileykovskaya E. Dowhan W. Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes.Chem. Phys. Lipids. 2014; 179: 42-48Crossref PubMed Scopus (175) Google Scholar]. Moreover, CL is required for the activity of ADP and Pi carriers, supplying substrate for ATP production [66.Claypool S.M. Cardiolipin, a critical determinant of mitochondrial carrier protein assembly and function.Biochim. Biophys. Acta Biomembr. 2009; 1788: 2059-2068Crossref PubMed Scopus (152) Google Scholar]. Finally, due to its dimeric polar head, CL acts as a proton trap supplying protons to ATP synthase while minimizing pH changes in the intermembrane space [67.Haines T.H. Dencher N.A. Cardiolipin: a proton trap for oxidative phosphorylation.FEBS Lett. 2002; 528: 35-39Crossref PubMed Scopus (316) Google Scholar]. Proapoptotic stimuli or pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS), can damage mitochondria and induce the translocation of CL from the IMM to the cytoplasmic side of the OMM (Figure 2A) and, to some extent, to the plasma membrane [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar,7.Manganelli V. et al.Altered traffic of cardiolipin during apoptosis: exposure on the cell surface as a trigger for 'antiphospholipid antibodies.'.J Immunol Res. 2015; 2015: 847985Crossref PubMed Scopus (21) Google Scholar, 8.Balasubramanian K. et al.Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity.Sci. Signal. 2015; 8ra95Crossref PubMed Scopus (59) Google Scholar, 9.Garcia Fernandez M. et al.Early changes in intramitochondrial cardiolipin distribution during apoptosis.Cell Growth Differ. 2002; 13: 449-455PubMed Google Scholar, 10.Elliott E.I. et al.Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming.J. Immunol. 2018; 200: 3047-3052Crossref PubMed Scopus (82) Google Scholar, 11.Chu C.T. et al.Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.Nat. Cell Biol. 2013; 15: 1197-1205Crossref PubMed Scopus (647) Google Scholar]. To be exposed towards the cytosol, after its synthesis, CL must move from the inner to the outer leaflet of the IMM, cross the intermembrane space, and finally move from the inner to the outer leaflet of the OMM. The first and third steps are probably mediated by phospholipid scramblase 3, whereas mitochondrial nucleoside diphosphate kinase D may act as a bridge between IMM and OMM [12.Kagan V.E. et al.Cardiolipin asymmetry, oxidation and signaling.Chem. Phys. Lipids. 2014; 179: 64-69Crossref PubMed Scopus (87) Google Scholar] (Figure 2A). The production of reactive oxygen species (ROS) induced by apoptotic stimuli and PAMPs or other signals may promote phospholipid-mobilizing enzymes and be responsible for the exposure of CL (Figure 2A). Double bonds in uCL hydrophobic chains may be oxidized by ROS, generating a variety of oxidized CL (oxCL) products [13.Tyurina Y.Y. et al.Characterization of cardiolipins and their oxidation products by LC-MS analysis.Chem. Phys. Lipids. 2014; 179: 3-10Crossref PubMed Scopus (34) Google Scholar,14.Kim J. et al.Cardiolipin: Characterization of distinct oxidized molecular species.J. Lipid Res. 2011; 52: 125-135Crossref PubMed Scopus (50) Google Scholar], which might be found in the OMM (Figure 2B). In this review, we focus on the emerging role of CL modification and exposure in the OMM in cell death and immune signaling, with a focus on the differences between CL with unsaturated, saturated, and oxidized chains. Damaged mitochondria release ROS and proapoptotic factors into the cytosol, inducing an excess of oxidative stress and cell death, unless they are promptly removed by intracellular autophagocytosis (mitophagy) [15.Schofield J.H. Schafer Z.T. Mitochondrial reactive oxygen species and mitophagy: a complex and nuanced relationship.Antioxid. Redox Signal. 2020; (Published online April 7, 2020. https://doi.org/10.1089/ars.2020.8058)Crossref PubMed Scopus (61) Google Scholar,16.Maiuri M.C. et al.Self-eating and self-killing: crosstalk between autophagy and apoptosis.Nat. Rev. Mol. Cell Biol. 2007; 8: 741-752Crossref PubMed Scopus (2840) Google Scholar]. Highly damaged mitochondria are also a source of proinflammatory oxidized mitochondrial DNA (mtDNA) [17.West A.P. Shadel G.S. Mitochondrial DNA in innate immune responses and inflammatory pathology.Nat. Rev. Immunol. 2017; 17: 363-375Crossref PubMed Scopus (480) Google Scholar]. Hence, mitophagy is also important to control inflammation. Mitophagy occurs upon recognition of exposed CL as an 'eat-me' signal by the microtubule-associated protein 1A/1B-light chain 3 (LC3) [11.Chu C.T. et al.Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.Nat. Cell Biol. 2013; 15: 1197-1205Crossref PubMed Scopus (647) Google Scholar,18.Antón Z. et al.Human Atg8-cardiolipin interactions in mitophagy: specific properties of LC3B, GABARAPL2 and GABARAP.Autophagy. 2016; 12: 2386-2403Crossref PubMed Scopus (52) Google Scholar] (Figure 2C). Interestingly, sCL and MLCL are less efficiently bound to LC3 than are uCL and oxCL [11.Chu C.T. et al.Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.Nat. Cell Biol. 2013; 15: 1197-1205Crossref PubMed Scopus (647) Google Scholar,18.Antón Z. et al.Human Atg8-cardiolipin interactions in mitophagy: specific properties of LC3B, GABARAPL2 and GABARAP.Autophagy. 2016; 12: 2386-2403Crossref PubMed Scopus (52) Google Scholar], suggesting that CL modification impairs mitophagy, inducing uncontrolled cell death or inflammation. Mitochondria are found under certain circumstances in the extracellular milieu, for example in human plasma [19.Al Amir Dache Z. et al.Blood contains circulating cell-free respiratory competent mitochondria.FASEB J. 2020; 34: 3616-3630Crossref PubMed Scopus (159) Google Scholar]. Extracellular mitochondria coated by both uCL and oxCL are efficiently engulfed by professional phagocytes through the receptor Cluster of Differentiation 36 (CD36) (Figure 2D). The process is dependent on CL exposure, because it is blocked by binding CL to Annexin V [8.Balasubramanian K. et al.Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity.Sci. Signal. 2015; 8ra95Crossref PubMed Scopus (59) Google Scholar]. Thus, CL exposure might mediate the removal of damaged mitochondria released by dying or injured cells [20.Nakajima A. et al.Mitochondrial extrusion through the cytoplasmic vacuoles during cell death.J. Biol. Chem. 2008; 283: 24128-24135Crossref PubMed Scopus (58) Google Scholar], which are a source of proinflammatory damage-associated molecular patterns (DAMPs), such as ATP, mtDNA ,and formyl-peptides [17.West A.P. Shadel G.S. Mitochondrial DNA in innate immune responses and inflammatory pathology.Nat. Rev. Immunol. 2017; 17: 363-375Crossref PubMed Scopus (480) Google Scholar]. In contrast with necrosis, necroptosis, or pyroptosis, which are types of cell death associated with the release of proinflammatory molecules [21.Broz P. et al.The gasdermins, a protein family executing cell death and inflammation.Nat. Rev. Immunol. 2020; 20: 143-157Crossref PubMed Scopus (530) Google Scholar], apoptosis is generally considered to be an anti-inflammatory or immunologically silent event because apoptotic cells do not leak their intracellular content, but instead release anti-inflammatory molecules and are promptly phagocytized [22.Szondy Z. et al.Anti-inflammatory mechanisms triggered by apoptotic cells during their clearance.Front. Immunol. 2017; 8: 909Crossref PubMed Scopus (109) Google Scholar]. The intrinsic apoptosis pathway is activated by stress signals. Pro-casp-8 is recruited to the OMM, where it is activated and cleaves Bcl-2 homology domain 3 interacting-domain death agonist (BID) [16.Maiuri M.C. et al.Self-eating and self-killing: crosstalk between autophagy and apoptosis.Nat. Rev. Mol. Cell Biol. 2007; 8: 741-752Crossref PubMed Scopus (2840) Google Scholar]. The C-terminal fragment of BID (tBID) binds B cell lymphoma protein 2 (Bcl-2)-associated X (BAX) and Bcl-2 antagonist/killer (BAK), inducing conformational changes that allow BAX/BAK oligomerization and the formation of pores in the OMM [23.Billen L.P. et al.Bid: a Bax-like BH3 protein.Oncogene. 2008; 27: S93-S104Crossref PubMed Scopus (209) Google Scholar]. Cytochrome c (cyt c) and second mitochondria-derived activator of Casp/direct inhibitor of apoptosis-binding protein (Smac/DIABLO) are released through these pores, which leads to the activation of casp-9 and apoptotic cell death [16.Maiuri M.C. et al.Self-eating and self-killing: crosstalk between autophagy and apoptosis.Nat. Rev. Mol. Cell Biol. 2007; 8: 741-752Crossref PubMed Scopus (2840) Google Scholar]. CL is vital for several of these processes. As mentioned earlier, apoptotic stimuli cause the exposure of CL to the OMM. Exposed CL facilitates pro-casp-8 recruitment to mitochondria and activation by forcing its proximity with other pro-casp-8 monomers and then self-cleavage (Figure 3). Indeed, the binding of pro-casp-8 to CL-containing liposomes is higher than to CL-depleted liposomes and results in the production of active casp-8, which strongly binds CL liposomes [24.Jalmar O. et al.Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid.PLoS ONE. 2013; 8e55250Crossref PubMed Scopus (23) Google Scholar]. Cells lacking functional TAZ have less uCL and more MLCL and sCLs than do wild-type cells. Although pro-casp-8 localization at the mitochondria in these cells is not affected, they show impaired processing of pro-casp-8, which results in decreased cyt c and Smac/DIABLO release and resistance to apoptosis [25.Gonzalvez F. et al.Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.J. Cell Biol. 2008; 183: 681-696Crossref PubMed Scopus (233) Google Scholar]. This demonstrates that a physiological level of mature uCL is necessary for casp-8 activity and the execution of apoptosis [25.Gonzalvez F. et al.Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.J. Cell Biol. 2008; 183: 681-696Crossref PubMed Scopus (233) Google Scholar]. After its cleavage by casp-8 or other proteases, tBID localizes to the mitochondria [23.Billen L.P. et al.Bid: a Bax-like BH3 protein.Oncogene. 2008; 27: S93-S104Crossref PubMed Scopus (209) Google Scholar]. This process is promoted by the exposure of CL in the OMM, since the addition of pro-casp-8 and BID to CL-containing liposomes resulted in the processing of casp-8 and BID, with consequent localization of tBID within the liposomes [24.Jalmar O. et al.Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid.PLoS ONE. 2013; 8e55250Crossref PubMed Scopus (23) Google Scholar]. Liposomes with OMM lipid composition without CL are unable to bind tBID, whereas the addition of CL results in binding similar to isolated mitochondria, with the binding increasing as the CL content increases [26.Lutter M. et al.Cardiolipin provides specificity for targeting of tBid to mitochondria.Nat. Cell Biol. 2000; 2: 754-756Crossref PubMed Scopus (411) Google Scholar]. Reduced CL levels in live cells result in a decrease in tBID localization at the mitochondria, and impaired tBID binding and cyt c release in isolated mitochondria [26.Lutter M. et al.Cardiolipin provides specificity for targeting of tBid to mitochondria.Nat. Cell Biol. 2000; 2: 754-756Crossref PubMed Scopus (411) Google Scholar]. Interestingly, tBID has no affinity for CL films [26.Lutter M. et al.Cardiolipin provides specificity for targeting of tBid to mitochondria.Nat. Cell Biol. 2000; 2: 754-756Crossref PubMed Scopus (411) Google Scholar], suggesting that the binding of tBID to CL containing membranes is not due to electrostatic interaction, but to the unique properties of the lipid environment in which CL is inserted (e.g., curvature and fluidity) [27.Epand R.F. et al.Cardiolipin clusters and membrane domain formation induced by mitochondrial proteins.J. Mol. Biol. 2007; 365: 968-980Crossref PubMed Scopus (82) Google Scholar]. CL is required not only for recruiting tBID, but also for effective tBID induction of BAX oligomerization and pore formation [28.Kuwana T. et al.Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.Cell. 2002; 111P331-342Abstract Full Text Full Text PDF Scopus (1227) Google Scholar] (Figure 3). Monomeric BAX associates with both CL-free and CL-containing liposomes, but forms pores only when both CL and tBID are present [28.Kuwana T. et al.Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.Cell. 2002; 111P331-342Abstract Full Text Full Text PDF Scopus (1227) Google Scholar]. Although the addition of preformed oligomeric BAX to liposomes is sufficient to form small pores even in the absence of CL, CL strongly increases BAX pore-forming activity [28.Kuwana T. et al.Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.Cell. 2002; 111P331-342Abstract Full Text Full Text PDF Scopus (1227) Google Scholar]. A recent study demonstrated that BAX forms oligomers in the absence of CL, but that CL is necessary for effective pore-forming activity [29.Lai Y-C. et al.The role of cardiolipin in promoting the membrane pore-forming activity of BAX oligomers.Biochim. Biophys. Acta Biomembr. 2019; 1861: 268-280Crossref PubMed Scopus (29) Google Scholar]. During apoptosis, a large percentage of CL is oxidized [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar]. OxCL liposomes bind tBID more strongly than uCL liposomes do, thus resulting in faster and extensive OMM permeabilization [30.Korytowski W. et al.Permeabilization of the mitochondrial outer membrane by Bax/Truncated Bid (tBid) proteins as sensitized by cardiolipin hydroperoxide translocation.J. Biol. Chem. 2011; 286: 26334-26343Crossref PubMed Scopus (80) Google Scholar]. Impaired CL oxidation decreases Smac/DIABLO release from isolated mitochondria, which is restored by the addition of oxCL [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar], suggesting that oxCL is required for effective pore formation (Figure 3). However, further studies are needed to determine the role of oxCL in casp-8 activity, tBID recruitment, and BAX oligomerization. In the presence of oxidizing agents, such as H2O2 or after chemical induction of apoptosis, cyt c selectively oxidizes CL [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar,31.Vladimirov G.K. et al.Structure of the complex of cytochrome c with cardiolipin in non-polar environment.Chem. Phys. Lipids. 2018; 214: 35-45Crossref PubMed Scopus (18) Google Scholar,32.Nomura K. et al.Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis.Biochem. J. 2000; 351: 183-193Crossref PubMed Scopus (0) Google Scholar]. Since uCL but not sCL and oxCL, binds cyt c [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar] and inhibiting CL oxidation in cells impairs cyt c release [32.Nomura K. et al.Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis.Biochem. J. 2000; 351: 183-193Crossref PubMed Scopus (0) Google Scholar], it is generally accepted that the presence of CL enhances the affinity of cyt c with the outer leaflet of the IMM, while CL oxidation causes the detachment of cyt c from the IMM (Figure 3). Free cyt c can now be released from the intermembrane space once OMM pores are formed [4.Kagan V.E. et al.Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (983) Google Scholar,31.Vladimirov G.K. et al.Structure of the complex of cytochrome c with cardiolipin in non-polar environment.Chem. Phys. Lipids. 2018; 214: 35-45Crossref PubMed Scopus (18) Google Scholar]. However, as discussed in the previous section, oxCL is required for pore formation. This indicates that the observed decrease in cyt c release following impaired CL oxidation might simply be due to defective pores. Thus, further studies are required to demonstrate whether the impairment of cyt c binding to CL is an important step in cyt c release and induction of apoptosis. Liposomes made with uCLs inhibit the secretions of a large spectrum of LPS-induced proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, Interleukin (IL)-1β and Interferon (IFN)-γ (Figure 4) [8.Balasubramanian K. et al.Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity.Sci. Signal. 2015; 8ra95Crossref PubMed Scopus (59) Google Scholar,33.Pizzuto M. et al.Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4.Cell. Mol. Life Sci. 2019; 76: 3667-3678Crossref PubMed Scopus (22) Google Scholar,34.Coats S.R. et al.Cardiolipins act as a selective barrier to Toll-like receptor 4 activation in the intestine.Appl. Environ. Microbiol. 2016; 82: 4264-4278Crossref PubMed Scopus (7) Google Scholar]. LPS is an endotoxin present in Gram-negative bacteria. It is recognized by the immune system through its binding to the TLR4/Myeloid Differentiation 2 (TLR4/MD2) transmembrane receptor [35.Barton G.M. Kagan J.C. A cell biological view of Toll-like receptor function: regulation through compartmentalization.Nat. Rev. Immunol. 2009; 9: 535-542Crossref PubMed Scopus (524) Google Scholar,36.Gay N.J. et al.Assembly and localization of Toll-like receptor signaling complexes.Nat. Rev. Immunol. 2014; 14: 546-558Crossref PubMed Scopus (506) Google Scholar]. The LPS immunostimulatory part, lipid A, is a polyacylated phospholipid linked to a polysaccharide polar head [37.Calabrese V. et al.Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles.Mol. Immunol. 2014; 14: 1-9Google Scholar]. Crystal structures have shown that lipid A inserts its lipid chains in a hydrophobic pocket of MD2, whereas the anionic polar head forms H bonds with both MD2 and TLR4. One lipid chain and part of the p
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