ATPaseTb2, a Unique Membrane-bound FoF1-ATPase Component, Is Essential in Bloodstream and Dyskinetoplastic Trypanosomes
The presence of the FoF1-ATP synthase in every aerobic organism suggests that evolution has settled on a basic blueprint for the complex rotary motor capable of synthesizing life’s universal energy currency—ATP. However, compared to yeast and mammalian models of the FoF1-ATP synthase, several recent studies have reported unique structural and functional features of this complex from organisms representing the clades of Chromalveolata, Archaeplastida and Excavata. One of the most striking cases is observed in trypanosomes, important parasites of humans and animals. Notably, the FoF1-ATP synthase/ATPase switches from synthesizing ATP in the insect vector life stage to hydrolyzing ATP in their mammalian hosts to generate the essential mitochondrial membrane potential (Δψm). Moreover, this indispensable FoF1-ATPase contains up to 14 trypanosome-specific subunits. Here we characterize one such novel subunit, ATPaseTb2. We demonstrate that this subunit is crucial for the survival of the infectious stage of trypanosomes, part of the fully assembled FoF1-complex and it is essential for maintaining the Δψm. Given the enzyme’s irreplaceable function and extraordinary composition, we believe that the FoF1-ATPase is an attractive drug target.
Vyšlo v časopise:
ATPaseTb2, a Unique Membrane-bound FoF1-ATPase Component, Is Essential in Bloodstream and Dyskinetoplastic Trypanosomes. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004660
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004660
Souhrn
The presence of the FoF1-ATP synthase in every aerobic organism suggests that evolution has settled on a basic blueprint for the complex rotary motor capable of synthesizing life’s universal energy currency—ATP. However, compared to yeast and mammalian models of the FoF1-ATP synthase, several recent studies have reported unique structural and functional features of this complex from organisms representing the clades of Chromalveolata, Archaeplastida and Excavata. One of the most striking cases is observed in trypanosomes, important parasites of humans and animals. Notably, the FoF1-ATP synthase/ATPase switches from synthesizing ATP in the insect vector life stage to hydrolyzing ATP in their mammalian hosts to generate the essential mitochondrial membrane potential (Δψm). Moreover, this indispensable FoF1-ATPase contains up to 14 trypanosome-specific subunits. Here we characterize one such novel subunit, ATPaseTb2. We demonstrate that this subunit is crucial for the survival of the infectious stage of trypanosomes, part of the fully assembled FoF1-complex and it is essential for maintaining the Δψm. Given the enzyme’s irreplaceable function and extraordinary composition, we believe that the FoF1-ATPase is an attractive drug target.
Zdroje
1. Jamonneau V, Ilboudo H, Kabore J, Kaba D, Koffi M, et al. (2012) Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal. PLoS Negl Trop Dis 6: e1691. doi: 10.1371/journal.pntd.0001691 22720107
2. Stuart K, Brun R, Croft S, Fairlamb A, Gurtler RE, et al. (2008) Kinetoplastids: related protozoan pathogens, different diseases. J Clin Invest 118: 1301–1310. doi: 10.1172/JCI33945 18382742
3. Steverding D (2008) The history of African trypanosomiasis. Parasit Vectors 1: 3. doi: 10.1186/1756-3305-1-3 18275594
4. Bringaud F, Riviere L, Coustou V (2006) Energy metabolism of trypanosomatids: adaptation to available carbon sources. Mol Biochem Parasitol 149: 1–9. 16682088
5. Besteiro S, Barrett MP, Riviere L, Bringaud F (2005) Energy generation in insect stages of Trypanosoma brucei: metabolism in flux. Trends Parasitol 21: 185–191. 15780841
6. Hannaert V, Bringaud F, Opperdoes FR, Michels PA (2003) Evolution of energy metabolism and its compartmentation in Kinetoplastida. Kinetoplastid Biol Dis 2: 11. 14613499
7. Brown SV, Hosking P, Li J, Williams N (2006) ATP synthase is responsible for maintaining mitochondrial membrane potential in bloodstream form Trypanosoma brucei. Eukaryot Cell 5: 45–53. 16400167
8. Guler JL, Kriegova E, Smith TK, Lukes J, Englund PT (2008) Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei. Mol Microbiol 67: 1125–1142. doi: 10.1111/j.1365-2958.2008.06112.x 18221265
9. Nolan DP, Voorheis HP (1992) The mitochondrion in bloodstream forms of Trypanosoma brucei is energized by the electrogenic pumping of protons catalysed by the F1F0-ATPase. Eur J Biochem 209: 207–216. 1327770
10. Huang G, Vercesi AE, Docampo R (2013) Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter. Nat Commun 4: 2865. doi: 10.1038/ncomms3865 24305511
11. Vercesi AE, Docampo R, Moreno SN (1992) Energization-dependent Ca2+ accumulation in Trypanosoma brucei bloodstream and procyclic trypomastigotes mitochondria. Mol Biochem Parasitol 56: 251–257. 1484549
12. Kovarova J, Horakova E, Changmai P, Vancova M, Lukes J (2014) Mitochondrial and nucleolar localization of cysteine desulfurase Nfs and the scaffold protein Isu in Trypanosoma brucei. Eukaryot Cell 13: 353–362. doi: 10.1128/EC.00235-13 24243795
13. Mazet M, Morand P, Biran M, Bouyssou G, Courtois P, et al. (2013) Revisiting the central metabolism of the bloodstream forms of Trypanosoma brucei: production of acetate in the mitochondrion is essential for parasite viability. PLoS Negl Trop Dis 7: e2587. doi: 10.1371/journal.pntd.0002587 24367711
14. Schnaufer A, Clark-Walker GD, Steinberg AG, Stuart K (2005) The F1-ATP synthase complex in bloodstream stage trypanosomes has an unusual and essential function. EMBO J 24: 4029–4040. 16270030
15. Buchet K, Godinot C (1998) Functional F1-ATPase essential in maintaining growth and membrane potential of human mitochondrial DNA-depleted rho degrees cells. J Biol Chem 273: 22983–22989. 9722521
16. Dean S, Gould MK, Dewar CE, Schnaufer AC (2013) Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes. Proc Natl Acad Sci U S A 110: 14741–14746. doi: 10.1073/pnas.1305404110 23959897
17. Brun R, Hecker H, Lun ZR (1998) Trypanosoma evansi and T. equiperdum: distribution, biology, treatment and phylogenetic relationship (a review). Vet Parasitol 79: 95–107. 9806490
18. Stuart KD (1971) Evidence for the retention of kinetoplast DNA in an acriflavine-induced dyskinetoplastic strain of Trypanosoma brucei which replicates the altered central element of the kinetoplast. J Cell Biol 49: 189–195. 4102002
19. Lai DH, Hashimi H, Lun ZR, Ayala FJ, Lukes J (2008) Adaptations of Trypanosoma brucei to gradual loss of kinetoplast DNA: Trypanosoma equiperdum and Trypanosoma evansi are petite mutants of T. brucei. Proc Natl Acad Sci U S A 105: 1999–2004. doi: 10.1073/pnas.0711799105 18245376
20. Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41: 1–16. doi: 10.1042/BST20110773 23356252
21. Devenish RJ, Prescott M, Rodgers AJ (2008) The structure and function of mitochondrial F1F0-ATP synthases. Int Rev Cell Mol Biol 267: 1–58. doi: 10.1016/S1937-6448(08)00601-1 18544496
22. Walker JE, Dickson VK (2006) The peripheral stalk of the mitochondrial ATP synthase. Biochim Biophys Acta 1757: 286–296. 16697972
23. Dickson VK, Silvester JA, Fearnley IM, Leslie AG, Walker JE (2006) On the structure of the stator of the mitochondrial ATP synthase. EMBO J 25: 2911–2918. 16791136
24. Vaidya AB, Mather MW (2009) Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol 63: 249–267. doi: 10.1146/annurev.micro.091208.073424 19575561
25. Lapaille M, Escobar-Ramirez A, Degand H, Baurain D, Rodriguez-Salinas E, et al. (2010) Atypical subunit composition of the chlorophycean mitochondrial F1FO-ATP synthase and role of Asa7 protein in stability and oligomycin resistance of the enzyme. Mol Biol Evol 27: 1630–1644. doi: 10.1093/molbev/msq049 20156838
26. Zikova A, Schnaufer A, Dalley RA, Panigrahi AK, Stuart KD (2009) The F(0)F(1)-ATP synthase complex contains novel subunits and is essential for procyclic Trypanosoma brucei. PLoS Pathog 5: e1000436. doi: 10.1371/journal.ppat.1000436 19436713
27. Mather MW, Henry KW, Vaidya AB (2007) Mitochondrial drug targets in apicomplexan parasites. Curr Drug Targets 8: 49–60. 17266530
28. Balabaskaran Nina P, Dudkina NV, Kane LA, van Eyk JE, Boekema EJ, et al. (2010) Highly divergent mitochondrial ATP synthase complexes in Tetrahymena thermophila. PLoS Biol 8: e1000418. doi: 10.1371/journal.pbio.1000418 20644710
29. Nishi A, Scherbaum OH (1962) Oxidative phosphorylation in synchronized cultures of Tetrahymena pyriformis. Biochim Biophys Acta 65: 419–424. 13938753
30. Uyemura SA, Luo S, Vieira M, Moreno SN, Docampo R (2004) Oxidative phosphorylation and rotenone-insensitive malate- and NADH-quinone oxidoreductases in Plasmodium yoelii yoelii mitochondria in situ. J Biol Chem 279: 385–393. 14561763
31. Vazquez-Acevedo M, Cardol P, Cano-Estrada A, Lapaille M, Remacle C, et al. (2006) The mitochondrial ATP synthase of chlorophycean algae contains eight subunits of unknown origin involved in the formation of an atypical stator-stalk and in the dimerization of the complex. J Bioenerg Biomembr 38: 271–282. 17160464
32. Hashimi H, Benkovicova V, Cermakova P, Lai DH, Horvath A, et al. (2010) The assembly of F(1)F(O)-ATP synthase is disrupted upon interference of RNA editing in Trypanosoma brucei. Int J Parasitol 40: 45–54. doi: 10.1016/j.ijpara.2009.07.005 19654010
33. Chi TB, Brown BS, Williams N (1998) Subunit 9 of the mitochondrial ATP synthase of Trypanosoma brucei is nuclearly encoded and developmentally regulated. Mol Biochem Parasitol 92: 29–38. 9574907
34. Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241: 779–786. 8944766
35. Biegert A, Mayer C, Remmert M, Soding J, Lupas AN (2006) The MPI Bioinformatics Toolkit for protein sequence analysis. Nucleic Acids Res 34: W335–339. 16845021
36. Norais N, Prome D, Velours J (1991) ATP synthase of yeast mitochondria. Characterization of subunit d and sequence analysis of the structural gene ATP7. J Biol Chem 266: 16541–16549. 1832157
37. Walker JE, Runswick MJ, Poulter L (1987) ATP synthase from bovine mitochondria. The characterization and sequence analysis of two membrane-associated sub-units and of the corresponding cDNAs. J Mol Biol 197: 89–100. 2890767
38. Nugent T, Jones DT (2009) Transmembrane protein topology prediction using support vector machines. BMC Bioinformatics 10: 159. doi: 10.1186/1471-2105-10-159 19470175
39. Vertommen D, Van Roy J, Szikora JP, Rider MH, Michels PA, et al. (2008) Differential expression of glycosomal and mitochondrial proteins in the two major life-cycle stages of Trypanosoma brucei. Mol Biochem Parasitol 158: 189–201. doi: 10.1016/j.molbiopara.2007.12.008 18242729
40. Ko YH, Delannoy M, Hullihen J, Chiu W, Pedersen PL (2003) Mitochondrial ATP synthasome. Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J Biol Chem 278: 12305–12309. 12560333
41. Meyer B, Wittig I, Trifilieff E, Karas M, Schagger H (2007) Identification of two proteins associated with mammalian ATP synthase. Mol Cell Proteomics 6: 1690–1699. 17575325
42. Chen Y, Hung CH, Burderer T, Lee GS (2003) Development of RNA interference revertants in Trypanosoma brucei cell lines generated with a double stranded RNA expression construct driven by two opposing promoters. Mol Biochem Parasitol 126: 275–279. 12615326
43. Bowler MW, Montgomery MG, Leslie AG, Walker JE (2006) How azide inhibits ATP hydrolysis by the F-ATPases. Proc Natl Acad Sci U S A 103: 8646–8649. 16728506
44. Appleby RD, Porteous WK, Hughes G, James AM, Shannon D, et al. (1999) Quantitation and origin of the mitochondrial membrane potential in human cells lacking mitochondrial DNA. Eur J Biochem 262: 108–116. 10231371
45. Garcia JJ, Ogilvie I, Robinson BH, Capaldi RA (2000) Structure, functioning, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation—Comparison with the enzyme in Rho(0) cells completely lacking mtDNA. Journal of Biological Chemistry 275: 11075–11081. 10753912
46. Wittig I, Meyer B, Heide H, Steger M, Bleier L, et al. (2010) Assembly and oligomerization of human ATP synthase lacking mitochondrial subunits a and A6L. Biochim Biophys Acta 1797: 1004–1011. doi: 10.1016/j.bbabio.2010.02.021 20188060
47. Stock D, Leslie AG, Walker JE (1999) Molecular architecture of the rotary motor in ATP synthase. Science 286: 1700–1705. 10576729
48. Strauss M, Hofhaus G, Schroder RR, Kuhlbrandt W (2008) Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J 27: 1154–1160. doi: 10.1038/emboj.2008.35 18323778
49. Arnold I, Pfeiffer K, Neupert W, Stuart RA, Schagger H (1998) Yeast mitochondrial F1F0-ATP synthase exists as a dimer: identification of three dimer-specific subunits. EMBO J 17: 7170–7178. 9857174
50. Burger G, Lang BF, Braun HP, Marx S (2003) The enigmatic mitochondrial ORF ymf39 codes for ATP synthase chain b. Nucleic Acids Res 31: 2353–2360. 12711680
51. Heazlewood JL, Whelan J, Millar AH (2003) The products of the mitochondrial orf25 and orfB genes are FO components in the plant F1FO ATP synthase. FEBS Lett 540: 201–205. 12681508
52. Miranda-Astudillo H, Cano-Estrada A, Vazquez-Acevedo M, Colina-Tenorio L, Downie-Velasco A, et al. (2014) Interactions of subunits Asa2, Asa4 and Asa7 in the peripheral stalk of the mitochondrial ATP synthase of the chlorophycean alga Polytomella sp. Biochim Biophys Acta 1837: 1–13. doi: 10.1016/j.bbabio.2013.08.001 23933283
53. van Lis R, Mendoza-Hernandez G, Groth G, Atteia A (2007) New insights into the unique structure of the F0F1-ATP synthase from the chlamydomonad algae Polytomella sp. and Chlamydomonas reinhardtii. Plant Physiol 144: 1190–1199. 17468226
54. Chevallet M, Lescuyer P, Diemer H, van Dorsselaer A, Leize-Wagner E, et al. (2006) Alterations of the mitochondrial proteome caused by the absence of mitochondrial DNA: A proteomic view. Electrophoresis 27: 1574–1583. 16548050
55. Orian JM, Hadikusumo RG, Marzuki S, Linnane AW (1984) Biogenesis of mitochondria: defective yeast H+-ATPase assembled in the absence of mitochondrial protein synthesis is membrane associated. J Bioenerg Biomembr 16: 561–581. 6242247
56. Paul MF, Velours J, Arselin de Chateaubodeau G, Aigle M, Guerin B (1989) The role of subunit 4, a nuclear-encoded protein of the F0 sector of yeast mitochondrial ATP synthase, in the assembly of the whole complex. Eur J Biochem 185: 163–171. 2553400
57. Rak M, Gokova S, Tzagoloff A (2011) Modular assembly of yeast mitochondrial ATP synthase. EMBO J 30: 920–930. doi: 10.1038/emboj.2010.364 21266956
58. Chen C, Ko Y, Delannoy M, Ludtke SJ, Chiu W, et al. (2004) Mitochondrial ATP synthasome: three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J Biol Chem 279: 31761–31768. 15166242
59. Alibu VP, Storm L, Haile S, Clayton C, Horn D (2005) A doubly inducible system for RNA interference and rapid RNAi plasmid construction in Trypanosoma brucei. Mol Biochem Parasitol 139: 75–82. 15610821
60. Wickstead B, Ersfeld K, Gull K (2002) Targeting of a tetracycline-inducible expression system to the transcriptionally silent minichromosomes of Trypanosoma brucei. Mol Biochem Parasitol 125: 211–216. 12467990
61. Surve S, Heestand M, Panicucci B, Schnaufer A, Parsons M (2012) Enigmatic presence of mitochondrial complex I in Trypanosoma brucei bloodstream forms. Eukaryot Cell 11: 183–193. doi: 10.1128/EC.05282-11 22158713
62. Borst P, Fase-Fowler F, Gibson WC (1987) Kinetoplast DNA of Trypanosoma evansi. Mol Biochem Parasitol 23: 31–38. 3033499
63. Wirtz E, Leal S, Ochatt C, Cross GA (1999) A tightly regulated inducible expression system for conditional gene knock-outs and dominant-negative genetics in Trypanosoma brucei. Mol Biochem Parasitol 99: 89–101. 10215027
64. Oeffinger M, Wei KE, Rogers R, DeGrasse JA, Chait BT, et al. (2007) Comprehensive analysis of diverse ribonucleoprotein complexes. Nat Methods 4: 951–956. 17922018
65. Panigrahi AK, Ogata Y, Zikova A, Anupama A, Dalley RA, et al. (2009) A comprehensive analysis of Trypanosoma brucei mitochondrial proteome. Proteomics 9: 434–450. doi: 10.1002/pmic.200800477 19105172
66. Panigrahi AK, Zikova A, Dalley RA, Acestor N, Ogata Y, et al. (2008) Mitochondrial complexes in Trypanosoma brucei: a novel complex and a unique oxidoreductase complex. Mol Cell Proteomics 7: 534–545. 18073385
67. Singha UK, Peprah E, Williams S, Walker R, Saha L, et al. (2008) Characterization of the mitochondrial inner membrane protein translocator Tim17 from Trypanosoma brucei. Mol Biochem Parasitol 159: 30–43. doi: 10.1016/j.molbiopara.2008.01.003 18325611
68. Vondruskova E, van den Burg J, Zikova A, Ernst NL, Stuart K, et al. (2005) RNA interference analyses suggest a transcript-specific regulatory role for mitochondrial RNA-binding proteins MRP1 and MRP2 in RNA editing and other RNA processing in Trypanosoma brucei. J Biol Chem 280: 2429–2438. 15504736
69. Hannaert V, Albert MA, Rigden DJ, da Silva Giotto MT, Thiemann O, et al. (2003) Kinetic characterization, structure modelling studies and crystallization of Trypanosoma brucei enolase. Eur J Biochem 270: 3205–3213. 12869196
70. Law RH, Manon S, Devenish RJ, Nagley P (1995) ATP synthase from Saccharomyces cerevisiae. Methods Enzymol 260: 133–163. 8592441
71. Wittig I, Karas M, Schagger H (2007) High resolution clear native electrophoresis for in-gel functional assays and fluorescence studies of membrane protein complexes. Mol Cell Proteomics 6: 1215–1225. 17426019
72. Acestor N, Zikova A, Dalley RA, Anupama A, Panigrahi AP, et al. (2011) Trypanosoma brucei Mitochondrial Respiratome: Composition and organization in procyclic form. Molecular Cell Proteomics resubmitted.
73. Acestor N, Panigrahi AK, Ogata Y, Anupama A, Stuart KD (2009) Protein composition of Trypanosoma brucei mitochondrial membranes. Proteomics 9: 5497–5508. doi: 10.1002/pmic.200900354 19834910
74. Mayhew TM, Lucocq JM (2008) Quantifying immunogold labelling patterns of cellular compartments when they comprise mixtures of membranes (surface-occupying) and organelles (volume-occupying). Histochem Cell Biol 129: 367–378. doi: 10.1007/s00418-007-0375-6 18180944
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2015 Číslo 2
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Control of Murine Cytomegalovirus Infection by γδ T Cells
- ATPaseTb2, a Unique Membrane-bound FoF1-ATPase Component, Is Essential in Bloodstream and Dyskinetoplastic Trypanosomes
- Rational Development of an Attenuated Recombinant Cyprinid Herpesvirus 3 Vaccine Using Prokaryotic Mutagenesis and In Vivo Bioluminescent Imaging
- Direct Binding of Retromer to Human Papillomavirus Type 16 Minor Capsid Protein L2 Mediates Endosome Exit during Viral Infection