Abstract
Cardiolipin is a key mitochondrial membrane phospholipid involved in the regulation of generation of ATP. Cardiolipin synthesis and remodeling are tightly regulated processes in eukaryotic cells. The role of phospholipases in the regulation of cardiolipin metabolism is becoming much clearer. Cardiolipin is hydrolysed by several classes of phospholipases including calcium-independent phospholipase A2, secretory phospholipase A2, and cytosolic phospholipase A2. Mitochondrial calcium-independent phospholipase A2 gamma has emerged as a key player not only in the regulated hydrolysis of cardiolipin to monolysocardiolipin, but also in the overall regulation of mitochondrial function and energy production. The purpose of this chapter is to summarize some of the more current findings on the role of phospholipases in the regulation of cardiolipin metabolism in the heart and mammalian tissues. In addition, a brief discussion on the role of exogenous phospholipase-treatment of cells on cardiolipin metabolism is presented.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
White DA (1973) Form and function of phospholipids. In: Ansell GB, Hawthorne JN, Dawson RM (eds) Phospholipids. Elsevier Biomedical, Amsterdam
Reig J, Domingo E, Segura R et al (1993) Rat myocardial tissue lipids and their effect on ventricular electrical activity: influence on dietary lipids. Cardiovasc Res 27:364–370
Hostetler KY (1982) Polyglycerophospholipids: phosphatidylglycerol, diphosphatidylglycerol and bis (monoacylglycero) phosphate. In: Hawthorne JN, Ansell GB (eds) Phospholipids. Elsevier, Amsterdam, p 215
Pangborn M (1942) Isolation and purification of a serologically active phospholipid from beef heart. J Biol Chem 143:247
Poorthuis BJ, Yazaki PJ, Hostetler KY (1976) An improved two dimensional thin-layer chromatography system for the separation of phosphatidylglycerol and its derivatives. J Lipid Res 17:433–437
Hatch GM (2004) Cell biology of cardiac mitochondrial phospholipids. Biochem Cell Biol 82:99–112
Hovius R, Lambrechts H, Nicolay K, de Kruijff B (1990) Improved methods to isolate and subfractionate rat liver mitochondria. Lipid composition of the inner and outer membrane. Biochim Biophys Acta 1021:217–226
Hovius R, Thijssen J, van der Linden P et al (1993) Phospholipid asymmetry of the outer membrane of rat liver mitochondria. Evidence for the presence of cardiolipin on the outside of the outer membrane. FEBS Lett 330:71–76
Stoffel W, Schiefer HG (1968) Biosynthesis and composition of phosphatides in outer and inner mitochondrial membranes. Hoppe Seylers Z Physiol Chem 349:1017–1026
Hoch FL (1992) Cardiolipins and biomembrane function. Biochim Biophys Acta 1113:71–133
Zhang M, Mileykovskaya E, Dowhan W (2002) Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane. J Biol Chem 277:43553–43556
Ascenzi P, Polticelli F, Marino M et al (2011) Cardiolipin drives cytochrome C proapoptotic and antiapoptotic actions. IUBMB Life 63:160–165
Gonzalvez F, Schug ZT, Houtkooper RH et al (2008) Cardiolipin provides an essential activating platform for caspase-8 on mitochondria. J Cell Biol 183:681–696
Christie DA, Lemke CD, Elias IM et al (2011) Stomatin-like protein 2 binds cardiolipin and regulates mitochondrial biogenesis and function. Mol Cell Biol 31:3845–3856
Yamaoka S, Urade R, Kito M (1990) Cardiolipin molecular species in rat heart mitochondria are sensitive to essential fatty acid-deficient dietary lipids. J Nutr 120:415–421
Ohtsuka T, Nishijima M, Suzuki K, Akamatsu Y (1993) Mitochondrial dysfunction of a cultured Chinese hamster ovary cell mutant deficient in cardiolipin. J Biol Chem 268:22914–22919
Petrosillo G, Ruggiero FM, Paradies G (2003) Role of reactive oxygen species and cardiolipin in the release of cytochrome C from mitochondria. FASEB J 17:2202–2208
Hatch GM (1998) Cardiolipin: biosynthesis, remodeling and trafficking in the heart and mammalian cells. Int J Mol Med 1:33–41
Osman C, Merkwirth C, Langer T (2009) Prohibitins and the functional compartmentalization of mitochondrial membranes. J Cell Sci 122:3823–3830
Osman C, Haag M, Wieland FT et al (2010) A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4. EMBO J 29:1976–1987
van Gestel RA, Rijken PJ, Surinova S et al (2010) The influence of the acyl chain composition of cardiolipin on the stability of mitochondrial complexes; an unexpected effect of cardiolipin in α-ketoglutarate dehydrogenase and prohibitin complexes. J Proteomics 73:806–814
Christie DA, Kirchhof MG, Vardhana S et al (2012) Mitochondrial and plasma membrane pools of stomatin-like protein 2 coalesce at the immunological synapse during T cell activation. PLoS One 7:e37144
Saini-Chohan HK, Dakshinamurti S, Taylor WA et al (2011) Persistent pulmonary hypertension results in reduced tetralinoleoyl-cardiolipin and mitochondrial complex II + III during the development of right ventricular hypertrophy in the neonatal pig heart. Am J Physiol Heart Circ Physiol 301:H1415–H1424
Hauff KD, Hatch GM (2006) Cardiolipin metabolism and Barth syndrome. Prog Lipid Res 45:91–101
Schlame M (2008) Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J Lipid Res 49:1607–1620
Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65:2493–2506
Hauff KD, Hatch GM (2010) Reduction in cholesterol synthesis in response to serum starvation in lymphoblasts of a patient with Barth syndrome. Biochem Cell Biol 88:595–602
Lu B, Kelher MR, Lee DP et al (2004) Complex expression pattern of the Barth syndrome gene product tafazzin in human cell lines and murine tissues. Biochem Cell Biol 82:569–576
Acehan D, Vaz F, Houtkooper RH et al (2011) Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J Biol Chem 286:899–908
Soustek MS, Falk DJ, Mah CS et al (2011) Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Hum Gene Ther 22:865–871
Brandner K, Mick DU, Frazier AE et al (2005) Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth syndrome. Mol Biol Cell 16:5202–5214
Ma L, Vaz FM, Gu Z et al (2004) The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome. J Biol Chem 279:44394–44399
Khuchua Z, Yue Z, Batts L, Strauss AW (2006) A zebrafish model of human Barth syndrome reveals the essential role of tafazzin in cardiac development and function. Circ Res 99:201–208
Xu Y, Zhang S, Malhotra A et al (2009) Characterization of tafazzin splice variants from humans and fruit flies. J Biol Chem 284:29230–29239
Hatch GM (1994) Cardiolipin biosynthesis in the isolated heart. Biochem J 297:201–208
Heacock AM, Uhler MD, Agranoff BW (1996) Cloning of CDP-diacylglycerol synthase from a human neuronal cell line. J Neurochem 67:2200–2203
Athea Y, Viollet B, Mateo P et al (2007) AMP-activated protein kinase α2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function. Diabetes 56:786–794
Jiang YJ, Lu B, Xu FY et al (2004) Stimulation of cardiac cardiolipin biosynthesis by PPARα activation. J Lipid Res 45:244–252
Hatch GM, Gu Y, Xu FY et al (2008) StARD13(Dlc-2) RhoGap mediates ceramide activation of phosphatidylglycerolphosphate synthase and drug response in Chinese hamster ovary cells. Mol Biol Cell 19:1083–1092
Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84:91–99
Xu FY, McBride H, Acehan D et al (2010) The dynamics of cardiolipin synthesis post-mitochondrial fusion. Biochim Biophys Acta 1798:1577–1585
Xiao J, Engel JL, Zhang J et al (2011) Structural and functional analysis of PTPMT1, a phosphatase required for cardiolipin synthesis. Proc Natl Acad Sci USA 108:11860–11865
Zhang J, Guan Z, Murphy AN et al (2011) Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis. Cell Metab 13:690–700
Hostetler KY, Van den Bosch H, Van Deenen LL (1971) Biosynthesis of cardiolipin in liver mitochondria. Biochim Biophys Acta 239:113–119
Schlame M, Haldar D (1993) Cardiolipin is synthesized on the matrix side of the inner membrane in rat liver mitochondria. J Biol Chem 268:74–79
Schlame M, Hostetler KY (1991) Solubilization, purification, and characterization of cardiolipin synthase from rat liver mitochondria. Demonstration of its phospholipid requirement. J Biol Chem 266:22398–22403
Lu B, Xu FY, Jiang YJ et al (2006) Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1). J Lipid Res 47:1140–1145
Chen D, Zhang XY, Shi Y (2006) Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria. Biochem J 398:169–176
Houtkooper RH, Akbari H, van Lenthe H et al (2006) Identification and characterization of human cardiolipin synthase. FEBS Lett 580:3059–3064
Lu B, Xu FY, Taylor WA et al (2011) Cardiolipin synthase-1 mRNA expression does not correlate with endogenous cardiolipin synthase enzyme activity in vitro and in vivo in mammalian lipopolysaccharide models of inflammation. Inflammation 34:247–254
Sparagna GC, Chicco AJ, Murphy RC et al (2007) Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. J Lipid Res 48:1559–1570
Lands WE (2000) Stories about acyl chains. Biochim Biophys Acta 1483:1–14
Buckland AG, Kinkaid AR, Wilton DC (1998) Cardiolipin hydrolysis by human phospholipases A2. The multiple enzymatic activities of human cytosolic phospholipase A2. Biochim Biophys Acta 1390:65–72
Mancuso DJ, Sims HF, Han X et al (2007) Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype. J Biol Chem 282:34611–34622
Seleznev K, Zhao C, Zhang XH et al (2006) Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine. J Biol Chem 281:22275–22288
Muralikrishna Adibhatla R, Hatcher JF (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40:376–387
Su H, McClarty G, Dong F et al (2004) Activation of Raf/MEK/ERK/cPLA2 signaling pathway is essential for chlamydial acquisition of host glycerophospholipids. J Biol Chem 279:9409–9416
Cao J, Liu Y, Lockwood J et al (2004) A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT-1) in mouse. J Biol Chem 279:31727–31734
Zhao Y, Chen YQ, Li S et al (2009) The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids. J Lipid Res 50:945–956
Li J, Romestaing C, Han X et al (2010) Cardiolipin remodeling by ALCAT-1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab 12:154–165
Saini-Chohan HK, Hatch GM (2009) Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure. Curr Drug Metab 10:206–219
Schlame M, Rustow B (1990) Lysocardiolipin formation and reacylation in isolated rat liver mitochondria. Biochem J 272:589–595
Ma BJ, Taylor WA, Dolinsky VW, Hatch GM (1999) Acylation of monolysocardiolipin in rat heart. J Lipid Res 40:1837–1845
Taylor WA, Hatch GM (2003) Purification and characterization of monolysocardiolipin acyltransferase from pig liver mitochondria. J Biol Chem 278:12716–12721
Taylor WA, Hatch GM (2009) Identification of the human mitochondrial linoleoyl-coenzyme A monolysocardiolipin acyltransferase (MLCL AT-1). J Biol Chem 284:30360–30371
Xu Y, Kelley RI, Blanck TJ, Schlame M (2003) Remodeling of cardiolipin by phospholipid transacylation. J Biol Chem 278:51380–51385
Xu Y, Malhotra A, Ren M, Schlame M (2006) The enzymatic function of tafazzin. J Biol Chem 281:39217–39224
Zhuravleva E, Gut H, Hynx D et al (2012) Acyl coenzyme A thioesterase Them5/Acot15 is involved in cardiolipin remodeling and fatty liver development. Mol Cell Biol 32:2685–2697
Zhang L, Bell RJ, Kiebish MA et al (2011) A mathematical model for the determination of steady-state cardiolipin remodeling mechanisms using lipidomic data. PLoS One 6:e21170
Hauff K, Linda D, Hatch GM (2009) Mechanism of the elevation in cardiolipin during HeLa cell entry into the S-phase of the human cell cycle. Biochem J 417:573–582
Taylor WA, Mejia EM, Mitchell RW et al (2012) Human trifunctional protein α links cardiolipin remodeling to β-oxidation. PLoS One 7:e48628
Xu FY, Kelly SL, Hatch GM (1999) N-Acetylsphingosine stimulates phosphatidylglycerolphosphate synthase activity in H9c2 cardiac cells. Biochem J 337:483–490
Degli Esposti M (2003) The mitochondrial battlefield and membrane lipids during cell death signalling. Ital J Biochem 52:43–50
Sorice M, Circella A, Cristea IM et al (2004) Cardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis. Cell Death Differ 11:1133–1145
Liu J, Durrant D, Yang HS et al (2005) The interaction between tBid and cardiolipin or monolysocardiolipin. Biochem Biophys Res Commun 330:865–870
Danos M, Taylor WA, Hatch GM (2008) Mitochondrial monolysocardiolipin acyltransferase is elevated in the surviving population of H9c2 cardiac myoblast cells exposed to 2-deoxyglucose-induced apoptosis. Biochem Cell Biol 86:11–20
Yasuda Y, Yoshinaga N, Murayama T, Nomura Y (1999) Inhibition of hydrogen peroxide-induced apoptosis but not arachidonic acid release in GH3 cell by EGF. Brain Res 850:197–206
Thang SH, Yasuda Y, Umezawa M et al (2000) Inhibition of phospholipase A2 activity by S-nitroso-cysteine in a cyclic GMP-independent manner in PC12 cells. Eur J Pharmacol 395:183–191
Fraiz J, Jones RB (1988) Chlamydial infections. Annu Rev Med 39:357–370
Wylie JL, Hatch GM, McClarty G (1997) Host cell phospholipids are trafficked to and then modified by Chlamydia trachomatis. J Bacteriol 179:7233–7242
Hatch GM, McClarty G (1998) Phospholipid composition of purified Chlamydia trachomatis mimics that of the eucaryotic host cell. Infect Immun 66:3727–3735
Hatch GM, McClarty G (2004) C. trachomatis-infection accelerates metabolism of phosphatidylcholine derived from low density lipoprotein but does not affect phosphatidylcholine secretion from hepatocytes. BMC Microbiol 4:8
Fischer K, Chatterjee D, Torrelles J et al (2001) Mycobacterial lysocardiolipin is exported from phagosomes upon cleavage of cardiolipin by a macrophage-derived lysosomal phospholipase A2. J Immunol 167:2187–2192
Zhao Z, Zhang X, Zhao C et al (2010) Protection of pancreatic beta-cells by group VIA phospholipase A2-mediated repair of mitochondrial membrane peroxidation. Endocrinology 151:3038–3048
McHowat J, Tappia PS, Liu S et al (2001) Redistribution and abnormal activity of phospholipase A2 isoenzymes in postinfarct congestive heart failure. Am J Physiol Cell Physiol 280:C573–C580
Zachman DK, Chicco AJ, McCune SA et al (2010) The role of calcium-independent phospholipase A2 in cardiolipin remodeling in the spontaneously hypertensive heart failure rat heart. J Lipid Res 51:525–534
Mancuso DJ, Kotzbauer P, Wozniak DF et al (2009) Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem 284:35632–35644
Yoda E, Hachisu K, Taketomi Y et al (2010) Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2γ-deficient mice. J Lipid Res 51:3003–3015
Mancuso DJ, Sims HF, Yang K et al (2010) Genetic ablation of calcium-independent phospholipase A2γ prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation. J Biol Chem 285:36495–36510
Therese P (2006) Persistent pulmonary hypertension of the newborn. Paediatr Respir Rev 7(suppl 1):S175–S176
Vosatka RJ (2002) Persistent pulmonary hypertension of the newborn. N Engl J Med 346:864
Xu FY, Taylor WA, Hatch GM (1998) Lysophosphatidylcholine inhibits cardiolipin biosynthesis in H9c2 cardiac myoblast cells. Arch Biochem Biophys 349:341–348
Xu FY, Kelly SL, Taylor WA, Hatch GM (1998) On the mechanism of the phospholipase C-mediated attenuation of cardiolipin biosynthesis in H9c2 cardiac myoblast cells. Mol Cell Biochem 188:217–223
Acknowledgements
This work was supported by HSFC and CIHR operating grants (Grant M. Hatch) and the DREAM Theme (Vernon W. Dolinsky and Grant M. Hatch). Edgard M. Mejia is the recipient of a University of Manitoba Tricouncil GETS graduate studentship. Grant M. Hatch is a Canada Research Chair in Molecular Cardiolipin Metabolism.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Mejia, E.M., Dolinsky, V.W., Hatch, G.M. (2014). Role of Phospholipases in Regulation of Cardiolipin Biosynthesis and Remodeling in the Heart and Mammalian Cells. In: Tappia, P., Dhalla, N. (eds) Phospholipases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0464-8_2
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0464-8_2
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-0463-1
Online ISBN: 978-1-4939-0464-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)