Skip to main content
Log in

Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Mitochondria move, fuse and divide in cells. The dynamic behavior of mitochondria is central to the control of their structure and function. Three conserved mitochondrial dynamin-related GTPases (i.e., mitofusin, Opa1 and Drp1 in mammals and Fzo1, Mgm1 and Dnm1 in yeast) mediate mitochondrial fusion and division. In addition to dynamins, recent studies demonstrated that phospholipids in mitochondria also play key roles in mitochondrial dynamics by interacting with dynamin GTPases and by directly changing the biophysical properties of the mitochondrial membranes. Changes in phospholipid composition also promote mitophagy, which is a selective mitochondrial degradation process that is mechanistically coupled to mitochondrial division. In this review, we will discuss the biogenesis and function of mitochondrial phospholipids.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159

    PubMed  CAS  Google Scholar 

  2. Yun J, Finkel T (2014) Mitohormesis. Cell Metab 19(5):757–766

  3. Sesaki H, Adachi Y, Kageyama Y, Itoh K, Iijima M (2013) In vivo functions of Drp1: Lessons learned from yeast genetics and mouse knockouts. Biochim Biophys Acta. doi:10.1016/j.bbadis.2013.11.024

  4. Lackner LL (2013) Determining the shape and cellular distribution of mitochondria: the integration of multiple activities. Curr Opin Cell Biol 25:471–476

    PubMed  CAS  Google Scholar 

  5. Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17:491–506

    PubMed  CAS  Google Scholar 

  6. Okamoto K, Shaw JM (2005) Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 39:503–536

  7. Elgass K, Pakay J, Ryan MT, Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochim Biophys Acta 1833:150–161

    PubMed  CAS  Google Scholar 

  8. Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

    PubMed  CAS  Google Scholar 

  9. Shutt TE, McBride HM (2013) Staying cool in difficult times: mitochondrial dynamics, quality control and the stress response. Biochim Biophys Acta 1833(2):417–424

  10. Otera H, Ishihara N, Mihara K (2013) New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta 1833:1256–1268

    PubMed  CAS  Google Scholar 

  11. Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23:64–71

    PubMed  CAS  PubMed Central  Google Scholar 

  12. Cho DH, Nakamura T, Lipton SA (2010) Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci 67:3435–3447

    PubMed  CAS  Google Scholar 

  13. Ong SB, Hall AR, Hausenloy DJ (2013) Mitochondrial dynamics in cardiovascular health and disease. Antioxid Redox Signal 19:400–414

    PubMed  CAS  PubMed Central  Google Scholar 

  14. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598

    PubMed  CAS  PubMed Central  Google Scholar 

  15. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 108:10190–10195

    PubMed  CAS  PubMed Central  Google Scholar 

  16. Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600

    PubMed  CAS  PubMed Central  Google Scholar 

  17. Wallace DC (2013) Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases. Philos Trans R Soc Lond B Biol Sci 368:20120267

    PubMed  PubMed Central  Google Scholar 

  18. Chen H, Chan DC (2010) Physiological functions of mitochondrial fusion. Ann NY Acad Sci 1201:21–25

    PubMed  CAS  Google Scholar 

  19. Kageyama Y, Zhang Z, Sesaki H (2011) Mitochondrial division: molecular machinery and physiological functions. Curr Opin Cell Biol 23:427–434

    PubMed  CAS  PubMed Central  Google Scholar 

  20. Sesaki H, Southard SM, Yaffe MP, Jensen RE (2003) Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane. Mol Biol Cell 14:2342–2356

    PubMed  CAS  PubMed Central  Google Scholar 

  21. Meeusen S, DeVay R, Block J, Cassidy-Stone A, Wayson S, McCaffery JM, Nunnari J (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127:383–395

    PubMed  CAS  Google Scholar 

  22. Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20:3525–3532

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Griparic L, van der Wel NN, Orozco IJ, Peters PJ, van der Bliek AM (2004) Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem 279:18792–18798

    PubMed  CAS  Google Scholar 

  24. Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746

    PubMed  CAS  Google Scholar 

  25. Hales KG, Fuller MT (1997) Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90:121–129

    PubMed  CAS  Google Scholar 

  26. Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT, Nunnari J, Shaw JM (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol 143:359–373

    PubMed  CAS  PubMed Central  Google Scholar 

  27. Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867–874

    PubMed  CAS  Google Scholar 

  28. Sesaki H, Jensen RE (2001) UGO1 encodes an outer membrane protein required for mitochondrial fusion. J Cell Biol 152:1123–1134

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Hoppins S, Horner J, Song C, McCaffery JM, Nunnari J (2009) Mitochondrial outer and inner membrane fusion requires a modified carrier protein. J Cell Biol 184:569–581

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Tamura Y, Itoh K, Sesaki H (2011) SnapShot: mitochondrial dynamics. Cell 145:1158, 1158.e151

  31. Gandre-Babbe S, van der Bliek AM (2008) The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 19:2402–2412

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Zhao J, Liu T, Jin S, Wang X, Qu M, Uhlen P, Tomilin N, Shupliakov O, Lendahl U, Nister M (2011) Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO J 30:2762–2778

    PubMed  CAS  PubMed Central  Google Scholar 

  33. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT (2011) MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep 12:565–573

    PubMed  CAS  PubMed Central  Google Scholar 

  34. Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420

    PubMed  CAS  PubMed Central  Google Scholar 

  35. Sesaki H, Jensen RE (1999) Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol 147:699–706

    PubMed  CAS  PubMed Central  Google Scholar 

  36. Hammermeister M, Schodel K, Westermann B (2010) Mdm36 is a mitochondrial fission-promoting protein in Saccharomyces cerevisiae. Mol Biol Cell 21:2443–2452

    PubMed  CAS  PubMed Central  Google Scholar 

  37. Cerveny KL, Studer SL, Jensen RE, Sesaki H (2007) Yeast mitochondrial division and distribution require the cortical num1 protein. Dev Cell 12:363–375

    PubMed  CAS  Google Scholar 

  38. Bleazard W, McCaffery JM, King EJ, Bale S, Mozdy A, Tieu Q, Nunnari J, Shaw JM (1999) The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1:298–304

    PubMed  CAS  PubMed Central  Google Scholar 

  39. Tieu Q, Okreglak V, Naylor K, Nunnari J (2002) The WD repeat protein, Mdv1p, functions as a molecular adaptor by interacting with Dnm1p and Fis1p during mitochondrial fission. J Cell Biol 158:445–452

    PubMed  CAS  PubMed Central  Google Scholar 

  40. Mozdy AD, McCaffery JM, Shaw JM (2000) Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J Cell Biol 151:367–380

    PubMed  CAS  PubMed Central  Google Scholar 

  41. Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (2011) Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev 67:103–118

    PubMed  CAS  PubMed Central  Google Scholar 

  42. Horvath SE, Daum G (2013) Lipids of mitochondria. Prog Lipid Res 52:590–614

    PubMed  CAS  Google Scholar 

  43. Osman C, Voelker DR, Langer T (2011) Making heads or tails of phospholipids in mitochondria. J Cell Biol 192:7–16

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D et al (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15:1197–1205

    PubMed  CAS  PubMed Central  Google Scholar 

  45. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124

    PubMed  PubMed Central  Google Scholar 

  46. de Kroon AI, Koorengevel MC, Goerdayal SS, Mulders PC, Janssen MJ, de Kruijff B (1999) Isolation and characterization of highly purified mitochondrial outer membranes of the yeast Saccharomyces cerevisiae (method). Mol Membr Biol 16:205–211

    PubMed  Google Scholar 

  47. Zinser E, Sperka-Gottlieb CD, Fasch EV, Kohlwein SD, Paltauf F, Daum G (1991) Phospholipid synthesis and lipid composition of subcellular membranes in the unicellular eukaryote Saccharomyces cerevisiae. J Bacteriol 173:2026–2034

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Zheng Z, Zou J (2001) The initial step of the glycerolipid pathway: identification of glycerol 3-phosphate/dihydroxyacetone phosphate dual substrate acyltransferases in Saccharomyces cerevisiae. J Biol Chem 276:41710–41716

    PubMed  CAS  Google Scholar 

  49. Pagac M, Vazquez HM, Bochud A, Roubaty C, Knopfli C, Vionnet C, Conzelmann A (2012) Topology of the microsomal glycerol-3-phosphate acyltransferase Gpt2p/Gat1p of Saccharomyces cerevisiae. Mol Microbiol 86:1156–1166

    PubMed  CAS  Google Scholar 

  50. Wendel AA, Lewin TM, Coleman RA (2009) Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis. Biochim Biophys Acta 1791:501–506

    PubMed  CAS  PubMed Central  Google Scholar 

  51. Leung DW (2001) The structure and functions of human lysophosphatidic acid acyltransferases. Front Biosci 6:D944–D953

    PubMed  CAS  Google Scholar 

  52. Benghezal M, Roubaty C, Veepuri V, Knudsen J, Conzelmann A (2007) SLC1 and SLC4 encode partially redundant acyl-coenzyme A 1-acylglycerol-3-phosphate O-acyltransferases of budding yeast. J Biol Chem 282:30845–30855

    PubMed  CAS  Google Scholar 

  53. Riekhof WR, Wu J, Jones JL, Voelker DR (2007) Identification and characterization of the major lysophosphatidylethanolamine acyltransferase in Saccharomyces cerevisiae. J Biol Chem 282:28344–28352

    PubMed  CAS  Google Scholar 

  54. Rose K, Rudge SA, Frohman MA, Morris AJ, Engebrecht J (1995) Phospholipase D signaling is essential for meiosis. Proc Natl Acad Sci USA 92:12151–12155

    PubMed  CAS  PubMed Central  Google Scholar 

  55. Han GS, O’Hara L, Siniossoglou S, Carman GM (2008) Characterization of the yeast DGK1-encoded CTP-dependent diacylglycerol kinase. J Biol Chem 283:20443–20453

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Cai J, Abramovici H, Gee SH, Topham MK (2009) Diacylglycerol kinases as sources of phosphatidic acid. Biochim Biophys Acta 1791:942–948

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Choi SY, Huang P, Jenkins GM, Chan DC, Schiller J, Frohman MA (2006) A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 8:1255–1262

    PubMed  CAS  Google Scholar 

  58. Hermansson M, Hokynar K, Somerharju P (2011) Mechanisms of glycerophospholipid homeostasis in mammalian cells. Prog Lipid Res 50:240–257

    PubMed  CAS  Google Scholar 

  59. Shen H, Dowhan W (1996) Reduction of CDP-diacylglycerol synthase activity results in the excretion of inositol by Saccharomyces cerevisiae. J Biol Chem 271:29043–29048

    PubMed  CAS  Google Scholar 

  60. Tamura Y, Harada Y, Nishikawa S, Yamano K, Kamiya M, Shiota T, Kuroda T, Kuge O, Sesaki H, Imai K et al (2013) Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria. Cell Metab 17:709–718

    PubMed  CAS  PubMed Central  Google Scholar 

  61. Inglis-Broadgate SL, Ocaka L, Banerjee R, Gaasenbeek M, Chapple JP, Cheetham ME, Clark BJ, Hunt DM, Halford S (2005) Isolation and characterization of murine Cds (CDP-diacylglycerol synthase) 1 and 2. Gene 356:19–31

    PubMed  CAS  Google Scholar 

  62. Nikawa J, Yamashita S (1984) Molecular cloning of the gene encoding CDPdiacylglycerol-inositol 3-phosphatidyl transferase in Saccharomyces cerevisiae. Eur J Biochem 143:251–256

    PubMed  CAS  Google Scholar 

  63. Letts VA, Klig LS, Bae-Lee M, Carman GM, Henry SA (1983) Isolation of the yeast structural gene for the membrane-associated enzyme phosphatidylserine synthase. Proc Natl Acad Sci USA 80:7279–7283

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Chang SC, Heacock PN, Clancey CJ, Dowhan W (1998) The PEL1 gene (renamed PGS1) encodes the phosphatidylglycero-phosphate synthase of Saccharomyces cerevisiae. J Biol Chem 273:9829–9836

    PubMed  CAS  Google Scholar 

  65. Osman C, Haag M, Wieland FT, Brugger B, Langer T (2010) A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4. EMBO J 29:1976–1987

    PubMed  CAS  PubMed Central  Google Scholar 

  66. Zhang J, Guan Z, Murphy AN, Wiley SE, Perkins GA, Worby CA, Engel JL, Heacock P, Nguyen OK, Wang JH et al (2011) Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis. Cell Metab 13:690–700

    PubMed  CAS  PubMed Central  Google Scholar 

  67. Houtkooper RH, Akbari H, van Lenthe H, Kulik W, Wanders RJ, Frentzen M, Vaz FM (2006) Identification and characterization of human cardiolipin synthase. FEBS Lett 580:3059–3064

    PubMed  CAS  Google Scholar 

  68. Chang SC, Heacock PN, Mileykovskaya E, Voelker DR, Dowhan W (1998) Isolation and characterization of the gene (CLS1) encoding cardiolipin synthase in Saccharomyces cerevisiae. J Biol Chem 273:14933–14941

    PubMed  CAS  Google Scholar 

  69. Tuller G, Hrastnik C, Achleitner G, Schiefthaler U, Klein F, Daum G (1998) YDL142c encodes cardiolipin synthase (Cls1p) and is non-essential for aerobic growth of Saccharomyces cerevisiae. FEBS Lett 421:15–18

    PubMed  CAS  Google Scholar 

  70. 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

    PubMed  CAS  PubMed Central  Google Scholar 

  71. Lu B, Xu FY, Jiang YJ, Choy PC, Hatch GM, Grunfeld C, Feingold KR (2006) Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1). J Lipid Res 47:1140–1145

    PubMed  CAS  Google Scholar 

  72. Tomohiro S, Kawaguti A, Kawabe Y, Kitada S, Kuge O (2009) Purification and characterization of human phosphatidylserine synthases 1 and 2. Biochem J 418:421–429

    PubMed  CAS  Google Scholar 

  73. Vance JE, Tasseva G (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim Biophys Acta 1831:543–554

    PubMed  CAS  Google Scholar 

  74. Clancey CJ, Chang SC, Dowhan W (1993) Cloning of a gene (PSD1) encoding phosphatidylserine decarboxylase from Saccharomyces cerevisiae by complementation of an Escherichia coli mutant. J Biol Chem 268:24580–24590

    PubMed  CAS  Google Scholar 

  75. Trotter PJ, Voelker DR (1995) Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae. J Biol Chem 270:6062–6070

    PubMed  CAS  Google Scholar 

  76. Gulshan K, Shahi P, Moye-Rowley WS (2010) Compartment-specific synthesis of phosphatidylethanolamine is required for normal heavy metal resistance. Mol Biol Cell 21:443–455

    PubMed  CAS  PubMed Central  Google Scholar 

  77. Kodaki T, Yamashita S (1987) Yeast phosphatidylethanolamine methylation pathway. Cloning and characterization of two distinct methyltransferase genes. J Biol Chem 262:15428–15435

    PubMed  CAS  Google Scholar 

  78. Kodaki T, Yamashita S (1989) Characterization of the methyltransferases in the yeast phosphatidylethanolamine methylation pathway by selective gene disruption. Eur J Biochem 185:243–251

    PubMed  CAS  Google Scholar 

  79. Schuiki I, Daum G (2009) Phosphatidylserine decarboxylases, key enzymes of lipid metabolism. IUBMB Life 61:151–162

    PubMed  CAS  Google Scholar 

  80. Vance JE (2013) MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta 1841:595–609

    PubMed  Google Scholar 

  81. Gibellini F, Smith TK (2010) The Kennedy pathway––De novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB Life 62:414–428

    PubMed  CAS  Google Scholar 

  82. Lykidis A (2007) Comparative genomics and evolution of eukaryotic phospholipid biosynthesis. Prog Lipid Res 46:171–199

    PubMed  CAS  Google Scholar 

  83. Han GS, Wu WI, Carman GM (2006) The Saccharomyces cerevisiae lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 281:9210–9218

    PubMed  CAS  PubMed Central  Google Scholar 

  84. de Brito OM, Scorrano L (2008) Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion. Antioxid Redox Signal 10:621–633

    PubMed  Google Scholar 

  85. Sugiura A, Nagashima S, Tokuyama T, Amo T, Matsuki Y, Ishido S, Kudo Y, McBride HM, Fukuda T, Matsushita N et al (2013) MITOL regulates endoplasmic reticulum–mitochondria contacts via Mitofusin2. Mol Cell 51:20–34

    PubMed  CAS  Google Scholar 

  86. Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325:477–481

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Kornmann B, Osman C, Walter P (2011) The conserved GTPase Gem1 regulates endoplasmic reticulum–mitochondria connections. Proc Natl Acad Sci USA 108:14151–14156

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Nguyen T, Lewandowska A, Choi JY, Markgraf DF, Junker M, Bilgin M, Ejsing CS, Voelker DR, Rapoport TA, Shaw JM (2012) Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance. Traffic 13:880–890

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Tamura Y, Endo T, Iijima M, Sesaki H (2009) Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria. J Cell Biol 185:1029–1045

    PubMed  CAS  PubMed Central  Google Scholar 

  90. Tamura Y, Iijima M, Sesaki H (2010) Mdm35p imports Ups proteins into the mitochondrial intermembrane space by functional complex formation. EMBO J 29:2875–2887

    PubMed  CAS  PubMed Central  Google Scholar 

  91. Potting C, Wilmes C, Engmann T, Osman C, Langer T (2010) Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. EMBO J 29:2888–2898

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Potting C, Tatsuta T, Konig T, Haag M, Wai T, Aaltonen MJ, Langer T (2013) TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab 18:287–295

    PubMed  CAS  Google Scholar 

  93. Sesaki H, Dunn CD, Iijima M, Shepard KA, Yaffe MP, Machamer CE, Jensen RE (2006) Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J Cell Biol 173:651–658

    PubMed  CAS  PubMed Central  Google Scholar 

  94. Osman C, Haag M, Potting C, Rodenfels J, Dip PV, Wieland FT, Brugger B, Westermann B, Langer T (2009) The genetic interactome of prohibitins: coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria. J Cell Biol 184:583–596

    PubMed  CAS  PubMed Central  Google Scholar 

  95. Connerth M, Tatsuta T, Haag M, Klecker T, Westermann B, Langer T (2012) Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. Science 338:815–818

    PubMed  CAS  Google Scholar 

  96. Tamura Y, Onguka O, Hobbs AE, Jensen RE, Iijima M, Claypool SM, Sesaki H (2012) Role for two conserved intermembrane space proteins, Ups1p and Ups2p, [corrected] in intra-mitochondrial phospholipid trafficking. J Biol Chem 287:15205–15218

    PubMed  CAS  PubMed Central  Google Scholar 

  97. Tamura Y, Onguka O, Itoh K, Endo T, Iijima M, Claypool SM, Sesaki H (2012) Phosphatidylethanolamine Biosynthesis in Mitochondria: phosphatidylserine (PS) trafficking is independent of a PS decarboxylase and intermembrane space proteins UPS1P and UPS2P. J Biol Chem 287:43961–43971

    PubMed  CAS  PubMed Central  Google Scholar 

  98. Ammar MR, Kassas N, Chasserot-Golaz S, Bader MF, Vitale N (2013) Lipids in regulated exocytosis: what are they doing? Front Endocrinol (Lausanne) 4:125

    Google Scholar 

  99. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–862

    PubMed  CAS  Google Scholar 

  100. Ohba Y, Sakuragi T, Kage-Nakadai E, Tomioka NH, Kono N, Imae R, Inoue A, Aoki J, Ishihara N, Inoue T et al (2013) Mitochondria-type GPAT is required for mitochondrial fusion. EMBO J 32:1265–1279

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Gimeno RE, Cao J (2008) Thematic review series: glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity. J Lipid Res 49:2079–2088

    PubMed  CAS  Google Scholar 

  102. Herlan M, Bornhovd C, Hell K, Neupert W, Reichert AS (2004) Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J Cell Biol 165:167–173

    PubMed  CAS  PubMed Central  Google Scholar 

  103. DeVay RM, Dominguez-Ramirez L, Lackner LL, Hoppins S, Stahlberg H, Nunnari J (2009) Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. J Cell Biol 186:793–803

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Rujiviphat J, Meglei G, Rubinstein JL, McQuibban GA (2009) Phospholipid association is essential for dynamin-related protein Mgm1 to function in mitochondrial membrane fusion. J Biol Chem 284:28682–28686

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Abutbul-Ionita I, Rujiviphat J, Nir I, McQuibban GA, Danino D (2012) Membrane tethering and nucleotide-dependent conformational changes drive mitochondrial genome maintenance (Mgm1) protein-mediated membrane fusion. J Biol Chem 287:36634–36638

    PubMed  CAS  PubMed Central  Google Scholar 

  106. Sesaki H, Southard SM, Hobbs AE, Jensen RE (2003) Cells lacking Pcp1p/Ugo2p, a rhomboid-like protease required for Mgm1p processing, lose mtDNA and mitochondrial structure in a Dnm1p-dependent manner, but remain competent for mitochondrial fusion. Biochem Biophys Res Commun 308:276–283

    PubMed  CAS  Google Scholar 

  107. McQuibban GA, Saurya S, Freeman M (2003) Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423:537–541

    PubMed  CAS  Google Scholar 

  108. Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25:2966–2977

    PubMed  CAS  PubMed Central  Google Scholar 

  109. Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D, Martinou JC, Westermann B, Rugarli EI, Langer T (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187:1023–1036

    PubMed  CAS  PubMed Central  Google Scholar 

  110. Song Z, Chen H, Fiket M, Alexander C, Chan DC (2007) OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178:749–755

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Ban T, Heymann JA, Song Z, Hinshaw JE, Chan DC (2010) OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet 19:2113–2122

    PubMed  CAS  PubMed Central  Google Scholar 

  112. Ban T, Heymann JA, Song Z, Hinshaw JE, Chan DC (2010) OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet 19:2113–2122

    PubMed  CAS  PubMed Central  Google Scholar 

  113. Claypool SM, Koehler CM (2012) The complexity of cardiolipin in health and disease. Trends Biochem Sci 37:32–41

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Li J, Romestaing C, Han X, Li Y, Hao X, Wu Y, Sun C, Liu X, Jefferson LS, Xiong J et al (2010) Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab 12:154–165

    PubMed  CAS  PubMed Central  Google Scholar 

  115. Li J, Liu X, Wang H, Zhang W, Chan DC, Shi Y (2012) Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression. Proc Natl Acad Sci USA 109:6975–6980

    PubMed  CAS  PubMed Central  Google Scholar 

  116. Steenbergen R, Nanowski TS, Beigneux A, Kulinski A, Young SG, Vance JE (2005) Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J Biol Chem 280:40032–40040

    PubMed  CAS  PubMed Central  Google Scholar 

  117. Kung C (2005) A possible unifying principle for mechanosensation. Nature 436:647–654

    PubMed  CAS  Google Scholar 

  118. Chan EY, McQuibban GA (2012) Phosphatidylserine decarboxylase 1 (Psd1) promotes mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and alternative topogenesis of mitochondrial genome maintenance protein 1 (Mgm1). J Biol Chem 287:40131–40139

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Joshi AS, Thompson MN, Fei N, Huttemann M, Greenberg ML (2012) Cardiolipin and mitochondrial phosphatidylethanolamine have overlapping functions in mitochondrial fusion in Saccharomyces cerevisiae. J Biol Chem 287:17589–17597

    PubMed  CAS  PubMed Central  Google Scholar 

  120. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158

    PubMed  CAS  PubMed Central  Google Scholar 

  121. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49 and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24(5):659–667

  122. Richter V, Palmer CS, Osellame LD, Singh AP, Elgass K, Stroud DA, Sesaki H, Kvansakul M, Ryan MT (2014) Structural and functional analysis of MiD51, a dynamin receptor required for mitochondrial fission. J Cell Biol 204:477–486

    PubMed  CAS  PubMed Central  Google Scholar 

  123. Koirala S, Guo Q, Kalia R, Bui HT, Eckert DM, Frost A, Shaw JM (2013) Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci USA 110:E1342–E1351

    PubMed  CAS  PubMed Central  Google Scholar 

  124. Loson OC, Liu R, Rome ME, Meng S, Kaiser JT, Shan SO, Chan DC (2014) The mitochondrial fission receptor MiD51 requires ADP as a cofactor. Structure 22:367–377

    PubMed  CAS  PubMed Central  Google Scholar 

  125. Tieu Q, Nunnari J (2000) Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division. J Cell Biol 151:353–366

    PubMed  CAS  PubMed Central  Google Scholar 

  126. Lackner LL, Ping H, Graef M, Murley A, Nunnari J (2013) Endoplasmic reticulum-associated mitochondria–cortex tether functions in the distribution and inheritance of mitochondria. Proc Natl Acad Sci USA 110:E458–E467

    PubMed  CAS  PubMed Central  Google Scholar 

  127. Cerveny KL, Studer SL, Jensen RE, Sesaki H (2007) Yeast mitochondrial division and distribution require the cortical num1 protein. Dev Cell 12:363–375

    PubMed  CAS  Google Scholar 

  128. Hammermeister M, Schodel K, Westermann B (2010) Mdm36 is a mitochondrial fission-promoting protein in Saccharomyces cerevisiae. Mol Biol Cell 21:2443–2452

    PubMed  CAS  PubMed Central  Google Scholar 

  129. Cerveny KL, McCaffery JM, Jensen RE (2001) Division of mitochondria requires a noverl DNM1-interacting protien, Net2p. Mol Biol Cell 12(2):309–321

  130. Lackner LL, Horner JS, Nunnari J (2009) Mechanistic analysis of a dynamin effector. Science 325:874–877

    PubMed  CAS  Google Scholar 

  131. Yoon Y, Pitts KR, McNiven MA (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol Biol Cell 12:2894–2905

    PubMed  CAS  PubMed Central  Google Scholar 

  132. Ingerman E, Perkins EM, Marino M, Mears JA, McCaffery JM, Hinshaw JE, Nunnari J (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol 170:1021–1027

    PubMed  CAS  PubMed Central  Google Scholar 

  133. Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol 18:20–26

    PubMed  CAS  PubMed Central  Google Scholar 

  134. Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, Fukaya M, Kensler TW, Iijima M, Sesaki H (2009) The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol 186:805–816

    PubMed  CAS  PubMed Central  Google Scholar 

  135. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525

    PubMed  CAS  Google Scholar 

  136. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204

    PubMed  CAS  PubMed Central  Google Scholar 

  137. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basanez G, Meda P et al (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889–901

    PubMed  CAS  PubMed Central  Google Scholar 

  138. Wells RC, Hill RB (2011) The cytosolic domain of Fis1 binds and reversibly clusters lipid vesicles. PLoS One 6:e21384

    PubMed  CAS  PubMed Central  Google Scholar 

  139. Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J et al (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem 286:20710–20726

    PubMed  CAS  PubMed Central  Google Scholar 

  140. Bayir H, Kapralov AA, Jiang J, Huang Z, Tyurina YY, Tyurin VA, Zhao Q, Belikova NA, Vlasova II, Maeda A et al (2009) Peroxidase mechanism of lipid-dependent cross-linking of synuclein with cytochrome c: protection against apoptosis versus delayed oxidative stress in Parkinson disease. J Biol Chem 284:15951–15969

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Cosentino K, Garcia-Saez AJ (2014) Mitochondrial alterations in apoptosis. Chem Phys Lipids 181C:62–75

    Google Scholar 

  142. Schug ZT, Gottlieb E (2009) Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta 1788:2022–2031

    PubMed  CAS  Google Scholar 

  143. Zhang T, Saghatelian A (2013) Emerging roles of lipids in BCL-2 family-regulated apoptosis. Biochim Biophys Acta 1831:1542–1554

    PubMed  CAS  Google Scholar 

  144. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380

    PubMed  CAS  PubMed Central  Google Scholar 

  145. Kageyama Y, Zhang Z, Roda R, Fukaya M, Wakabayashi J, Wakabayashi N, Kensler TW, Reddy PH, Iijima M, Sesaki H (2012) Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. J Cell Biol 197:535–551

    PubMed  CAS  PubMed Central  Google Scholar 

  146. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    PubMed  CAS  PubMed Central  Google Scholar 

  147. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221

    PubMed  CAS  PubMed Central  Google Scholar 

  148. McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA (2014) Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J 33:282–295

    PubMed  CAS  Google Scholar 

  149. Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM (2012) A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol CB 22:135–141

    CAS  Google Scholar 

  150. Sterky FH, Lee S, Wibom R, Olson L, Larsson NG (2011) Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc Natl Acad Sci USA 108:12937–12942

    PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are grateful to a number of researchers who advanced our understanding of phospholipid biogenesis and mitochondrial fusion, division and mitophagy, and we apologize that we were not able to include all of the relevant studies due to space limitations. This work was supported by Grants from the NIH (GM084015 to MI and GM089853 and NS084154 to HS).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiromi Sesaki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Tamura, Y., Roy, M. et al. Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy. Cell. Mol. Life Sci. 71, 3767–3778 (2014). https://doi.org/10.1007/s00018-014-1648-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1648-6

Keywords

Navigation