Mitochondria Restrict Growth of the Intracellular Parasite Toxoplasma gondii by Limiting Its Uptake of Fatty Acids

Cell Metabolism

Volumn 27, Issue 4, 2018, Pages 886-897.e4

  Pernas, Lena ^a,b   Bean, Camilla ^a,b   Boothroyd, John C ^c   Scorrano, Luca ^a,b  

^a UNIVERSITY OF PADOVA   (Italy)

^b VENETIAN INSTITUTE OF MOLECULAR MEDICINE   (Italy)

^c STANFORD UNIVERSITY   (United States)

Author keywords

autophagy; fusion; lipid droplets; lipid metabolism; lipophagy; mitochondria; parasite; Toxoplasma gondii; oxidation

Indexed keywords

FAT DROPLET; FATTY ACID; TRIACYLGLYCEROL;

ARTICLE; AUTOPHAGY; CELL PROLIFERATION; CONTROLLED STUDY; DEFENSE MECHANISM; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; GENETICS; HOST CELL; LIPID STORAGE; LIPOPHAGOCYTOSIS; MICROBIAL GROWTH; MITOCHONDRION; MOLECULAR IMAGING; NONHUMAN; NUTRIENT; PRIORITY JOURNAL; TOXOPLASMA GONDII; ANIMAL; CACO-2 CELL LINE; FIBROBLAST; GROWTH, DEVELOPMENT AND AGING; HUMAN; IMMUNOLOGY; METABOLISM; MITOCHONDRIAL DYNAMICS; MOUSE; PARASITOLOGY; TOXOPLASMA; TOXOPLASMOSIS;

ANIMALS; AUTOPHAGY; CACO-2 CELLS; FATTY ACIDS; FIBROBLASTS; HUMANS; LIPID DROPLETS; MICE; MITOCHONDRIA; MITOCHONDRIAL DYNAMICS; TOXOPLASMA; TOXOPLASMOSIS;

EID: 85043452298     PISSN: 15504131     EISSN: 19327420     Source Type: Journal    
DOI: 10.1016/j.cmet.2018.02.018     Document Type: Article

References (72)

1. Abu Kwaik, Y., Bumann, D., Host delivery of favorite meals for intracellular pathogens. PLoS Pathog., 11, 2015, e1004866.
2. Andrade, R.M., Wessendarp, M., Gubbels, M.J., Striepen, B., Subauste, C.S., CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116 (2006), 2366–2377.
3. Black, M.W., Boothroyd, J.C., Lytic cycle of Toxoplasma gondii. Microbiol. Mol. Biol. Rev. 64 (2000), 607–623.
4. Brieland, J.K., Fantone, J.C., Remick, D.G., LeGendre, M., McClain, M., Engleberg, N.C., The role of Legionella pneumophila-infected Hartmannella vermiformis as an infectious particle in a murine model of Legionnaire's disease. Infect. Immun. 65 (1997), 5330–5333.
5. Caffaro, C.E., Boothroyd, J.C., Evidence for host cells as the major contributor of lipids in the intravacuolar network of Toxoplasma-infected cells. Eukaryot. Cell 10 (2011), 1095–1099.
6. Charron, A.J., Sibley, L.D., Host cells: mobilizable lipid resources for the intracellular parasite Toxoplasma gondii. J. Cell Sci. 115 (2002), 3049–3059.
7. Chen, H., Detmer, S.A., Ewald, A.J., Griffin, E.E., Fraser, S.E., Chan, D.C., Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160 (2003), 189–200.
8. Chowdhury, S.R., Reimer, A., Sharan, M., Kozjak-Pavlovic, V., Eulalio, A., Prusty, B.K., Fraunholz, M., Karunakaran, K., Rudel, T., Chlamydia preserves the mitochondrial network necessary for replication via microRNA-dependent inhibition of fission. J. Cell Biol. 216 (2017), 1071–1089.
9. Cipolat, S., Martins de Brito, O., Dal Zilio, B., Scorrano, L., OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl. Acad. Sci. USA 101 (2004), 15927–15932.
10. Cocchiaro, J.L., Kumar, Y., Fischer, E.R., Hackstadt, T., Valdivia, R.H., Cytoplasmic lipid droplets are translocated into the lumen of the Chlamydia trachomatis parasitophorous vacuole. Proc. Natl. Acad. Sci. USA 105 (2008), 9379–9384.
11. Coppens, I., Sinai, A.P., Joiner, K.A., Toxoplasma gondii exploits host low-density lipoprotein receptor-mediated endocytosis for cholesterol acquisition. J. Cell Biol. 149 (2000), 167–180.
12. Currie, E., Schulze, A., Zechner, R., Walther, T.C., Farese, R.V. Jr., Cellular fatty acid metabolism and cancer. Cell Metab. 18 (2013), 153–161.
13. Deretic, V., Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol. Rev. 240 (2011), 92–104.
14. Derouin, F., Chastang, C., In vitro effects of folate inhibitors on Toxoplasma gondii. Antimicrob. Agents Chemother. 33 (1989), 1753–1759.
15. Dumoux, M., Hayward, R.D., Membrane contact sites between pathogen-containing compartments and host organelles. Biochim. Biophys. Acta 1861 (2016), 895–899.
16. Escoll, P., Song, O.R., Viana, F., Steiner, B., Lagache, T., Olivo-Marin, J.C., Impens, F., Brodin, P., Hilbi, H., Buchrieser, C., Legionella pneumophila modulates mitochondrial dynamics to trigger metabolic repurposing of infected macrophages. Cell Host Microbe 22 (2017), 302–316.e7.
17. Farese, R.V. Jr., Walther, T.C., Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 139 (2009), 855–860.
18. Favaretto, F., Milan, G., Collin, G.B., Marshall, J.D., Stasi, F., Maffei, P., Vettor, R., Naggert, J.K., GLUT4 defects in adipose tissue are early signs of metabolic alterations in Alms1GT/GT, a mouse model for obesity and insulin resistance. PLoS One, 9, 2014, e109540.
19. Fox, B.A., Gigley, J.P., Bzik, D.J., Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation. Int. J. Parasitol. 34 (2004), 323–331.
20. Friis, R.R., Interaction of L cells and Chlamydia psittaci: entry of the parasite and host responses to its development. J. Bacteriol. 110 (1972), 706–721.
21. Fujimoto, Y., Onoduka, J., Homma, K.J., Yamaguchi, S., Mori, M., Higashi, Y., Makita, M., Kinoshita, T., Noda, J., Itabe, H., et al. Long-chain fatty acids induce lipid droplet formation in a cultured human hepatocyte in a manner dependent of Acyl-CoA synthetase. Biol. Pharm. Bull. 29 (2006), 2174–2180.
22. Gao, D., Zhang, J., Zhao, J., Wen, H., Pan, J., Zhang, S., Fang, Y., Li, X., Cai, Y., Wang, X., et al. Autophagy activated by Toxoplasma gondii infection in turn facilitates Toxoplasma gondii proliferation. Parasitol. Res. 113 (2014), 2053–2058.
23. Gomes, L.C., Di Benedetto, G., Scorrano, L., During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13 (2011), 589–598.
24. Hacker, C., Howell, M., Bhella, D., Lucocq, J., Strategies for maximizing ATP supply in the microsporidian Encephalitozoon cuniculi: direct binding of mitochondria to the parasitophorous vacuole and clustering of the mitochondrial porin VDAC. Cell Microbiol. 16 (2014), 565–579.
25. Harris, C.A., Haas, J.T., Streeper, R.S., Stone, S.J., Kumari, M., Yang, K., Han, X., Brownell, N., Gross, R.W., Zechner, R., et al. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J. Lipid Res. 52 (2011), 657–667.
26. Herms, A., Bosch, M., Reddy, B.J., Schieber, N.L., Fajardo, A., Ruperez, C., Fernandez-Vidal, A., Ferguson, C., Rentero, C., Tebar, F., et al. AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. Nat. Commun., 6, 2015, 7176.
27. Horwitz, M.A., Formation of a novel phagosome by the Legionnaires' disease bacterium (Legionella pneumophila). J. Exp. Med. 158 (1983), 1319–1331.
28. Jones, T.C., Hirsch, J.G., The interaction between Toxoplasma gondii and mammalian cells. II. The absence of lysosomal fusion with phagocytic vacuoles containing living parasites. J. Exp. Med. 136 (1972), 1173–1194.
29. Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., Akira, S., IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6 (2005), 981–988.
30. Kofoed, E.M., Vance, R.E., Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477 (2011), 592–595.
31. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169 (2005), 425–434.
32. Koshy, A.A., Fouts, A.E., Lodoen, M.B., Alkan, O., Blau, H.M., Boothroyd, J.C., Toxoplasma secreting Cre recombinase for analysis of host-parasite interactions. Nat. Methods 7 (2010), 307–309.
33. Late de Late, P., Pineda, M., Harnett, M., Harnett, W., Besteiro, S., Langsley, G., Apicomplexan autophagy and modulation of autophagy in parasite-infected host cells. Biomed. J. 40 (2017), 23–30.
34. Leanza, L., Romio, M., Becker, K.A., Azzolini, M., Trentin, L., Manago, A., Venturini, E., Zaccagnino, A., Mattarei, A., Carraretto, L., et al. Direct pharmacological targeting of a mitochondrial ion channel selectively kills tumor cells in vivo. Cancer Cell 31 (2017), 516–531.e10.
35. Lopaschuk, G.D., Wall, S.R., Olley, P.M., Davies, N.J., Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ. Res. 63 (1988), 1036–1043.
36. Mayer, N., Schweiger, M., Romauch, M., Grabner, G.F., Eichmann, T.O., Fuchs, E., Ivkovic, J., Heier, C., Mrak, I., Lass, A., et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nat. Chem. Biol. 9 (2013), 785–787.
37. Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., Tschopp, J., Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 (2005), 1167–1172.
38. Montoya, J.G., Liesenfeld, O., Toxoplasmosis. Lancet 363 (2004), 1965–1976.
39. Mota, L.A., Roberto Neto, J., Monteiro, V.G., Lobato, C.S., Oliveira, M.A., Cunha, M., D'Avila, H., Seabra, S.H., Bozza, P.T., DaMatta, R.A., Culture of mouse peritoneal macrophages with mouse serum induces lipid bodies that associate with the parasitophorous vacuole and decrease their microbicidal capacity against Toxoplasma gondii. Mem. Inst. Oswaldo Cruz 109 (2014), 767–774.
40. Naon, D., Zaninello, M., Giacomello, M., Varanita, T., Grespi, F., Lakshminaranayan, S., Serafini, A., Semenzato, M., Herkenne, S., Hernandez-Alvarez, M.I., et al. Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc. Natl. Acad. Sci. USA 113 (2016), 11249–11254.
41. Nguyen, T.B., Louie, S.M., Daniele, J.R., Tran, Q., Dillin, A., Zoncu, R., Nomura, D.K., Olzmann, J.A., DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy. Dev. Cell 42 (2017), 9–21.e5.
42. Nolan, S.J., Romano, J.D., Coppens, I., Host lipid droplets: an important source of lipids salvaged by the intracellular parasite Toxoplasma gondii. PLoS Pathog., 13, 2017, e1006362.
43. Onoguchi, K., Onomoto, K., Takamatsu, S., Jogi, M., Takemura, A., Morimoto, S., Julkunen, I., Namiki, H., Yoneyama, M., Fujita, T., Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1. PLoS Pathog., 6, 2010, e1001012.
44. Patten, D.A., Wong, J., Khacho, M., Soubannier, V., Mailloux, R.J., Pilon-Larose, K., MacLaurin, J.G., Park, D.S., McBride, H.M., Trinkle-Mulcahy, L., et al. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 33 (2014), 2676–2691.
45. Pernas, L., Adomako-Ankomah, Y., Shastri, A.J., Ewald, S.E., Treeck, M., Boyle, J.P., Boothroyd, J.C., Toxoplasma effector MAF1 mediates recruitment of host mitochondria and impacts the host response. PLoS Biol., 12, 2014, e1001845.
46. Pernas, L., Scorrano, L., Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu. Rev. Physiol. 78 (2016), 505–531.
47. Peyron, P., Vaubourgeix, J., Poquet, Y., Levillain, F., Botanch, C., Bardou, F., Daffe, M., Emile, J.F., Marchou, B., Cardona, P.J., et al. Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog., 4, 2008, e1000204.
48. Rabhi, S., Rabhi, I., Trentin, B., Piquemal, D., Regnault, B., Goyard, S., Lang, T., Descoteaux, A., Enninga, J., Guizani-Tabbane, L., Lipid droplet formation, their localization and dynamics during Leishmania major macrophage infection. PLoS One, 11, 2016, e0148640.
49. Ramakrishnan, S., Docampo, M.D., Macrae, J.I., Pujol, F.M., Brooks, C.F., van Dooren, G.G., Hiltunen, J.K., Kastaniotis, A.J., McConville, M.J., Striepen, B., Apicoplast and endoplasmic reticulum cooperate in fatty acid biosynthesis in apicomplexan parasite Toxoplasma gondii. J. Biol. Chem. 287 (2012), 4957–4971.
50. Ramakrishnan, S., Docampo, M.D., MacRae, J.I., Ralton, J.E., Rupasinghe, T., McConville, M.J., Striepen, B., The intracellular parasite Toxoplasma gondii depends on the synthesis of long-chain and very long-chain unsaturated fatty acids not supplied by the host cell. Mol. Microbiol. 97 (2015), 64–76.
51. Rambold, A.S., Cohen, S., Lippincott-Schwartz, J., Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32 (2015), 678–692.
52. Rambold, A.S., Kostelecky, B., Elia, N., Lippincott-Schwartz, J., Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc. Natl. Acad. Sci. USA 108 (2011), 10190–10195.
53. Reggiori, F., Klionsky, D.J., Autophagy in the eukaryotic cell. Eukaryot. Cell 1 (2002), 11–21.
54. Rizk, A., Paul, G., Incardona, P., Bugarski, M., Mansouri, M., Niemann, A., Ziegler, U., Berger, P., Sbalzarini, I.F., Segmentation and quantification of subcellular structures in fluorescence microscopy images using Squassh. Nat. Protoc. 9 (2014), 586–596.
55. Rohwedder, A., Zhang, Q., Rudge, S.A., Wakelam, M.J., Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. J. Cell Sci. 127 (2014), 3104–3115.
56. Romano, J.D., Sonda, S., Bergbower, E., Smith, M.E., Coppens, I., Toxoplasma gondii salvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole. Mol. Biol. Cell 24 (2013), 1974–1995.
57. Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9 (2012), 676–682.
58. Seth, R.B., Sun, L., Ea, C.K., Chen, Z.J., Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122 (2005), 669–682.
59. Sinai, A.P., Webster, P., Joiner, K.A., Association of host cell endoplasmic reticulum and mitochondria with the Toxoplasma gondii parasitophorous vacuole membrane: a high affinity interaction. J. Cell Sci. 110 (1997), 2117–2128.
60. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., Czaja, M.J., Autophagy regulates lipid metabolism. Nature 458 (2009), 1131–1135.
61. Sonda, S., Ting, L.M., Novak, S., Kim, K., Maher, J.J., Farese, R.V. Jr., Ernst, J.D., Cholesterol esterification by host and parasite is essential for optimal proliferation of Toxoplasma gondii. J. Biol. Chem. 276 (2001), 34434–34440.
62. Song, M., Mihara, K., Chen, Y., Scorrano, L., Dorn, G.W. 2nd, Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. 21 (2015), 273–285.
63. Souto, X.M., Barbosa, H.S., Menna-Barreto, R.F., The morphological analysis of autophagy in primary skeletal muscle cells infected with Toxoplasma gondii. Parasitol. Res. 115 (2016), 2853–2861.
64. Stavru, F., Bouillaud, F., Sartori, A., Ricquier, D., Cossart, P., Listeria monocytogenes transiently alters mitochondrial dynamics during infection. Proc. Natl. Acad. Sci. USA 108 (2011), 3612–3617.
65. Steele, S., Brunton, J., Kawula, T., The role of autophagy in intracellular pathogen nutrient acquisition. Front. Cell. Infect. Microbiol., 5, 2015, 51.
66. Suzuki, M., Danilchanka, O., Mekalanos, J.J., Vibrio cholerae T3SS effector VopE modulates mitochondrial dynamics and innate immune signaling by targeting Miro GTPases. Cell Host Microbe 16 (2014), 581–591.
67. Syn, G., Anderson, D., Blackwell, J.M., Jamieson, S.E., Toxoplasma gondii infection is associated with mitochondrial dysfunction in-vitro. Front. Cell. Infect. Microbiol., 7, 2017, 512.
68. Sznaidman, M.L., Haffner, C.D., Maloney, P.R., Fivush, A., Chao, E., Goreham, D., Sierra, M.L., LeGrumelec, C., Xu, H.E., Montana, V.G., et al. Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)—synthesis and biological activity. Bioorg. Med. Chem. Lett. 13 (2003), 1517–1521.
69. Tymoshenko, S., Oppenheim, R.D., Agren, R., Nielsen, J., Soldati-Favre, D., Hatzimanikatis, V., Metabolic needs and capabilities of Toxoplasma gondii through combined computational and experimental analysis. PLoS Comput. Biol., 11, 2015, e1004261.
70. Walther, T.C., Farese, R.V. Jr., Lipid droplets and cellular lipid metabolism. Annu. Rev. Biochem. 81 (2012), 687–714.
71. Wang, Y., Weiss, L.M., Orlofsky, A., Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth. J. Biol. Chem. 284 (2009), 1694–1701.
72. Xu, L.G., Wang, Y.Y., Han, K.J., Li, L.Y., Zhai, Z., Shu, H.B., VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19 (2005), 727–740.