title: Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase.
abstract: Mitochondrial ATP synthase is driven by chemiosmotic oxidation of pyruvate derived from glycolysis. Blood-stage malaria parasites eschew chemiosmosis, instead relying almost solely on glycolysis for their ATP generation, which begs the question of whether mitochondrial ATP synthase is necessary during the blood stage of the parasite life cycle. We knocked out the mitochondrial ATP synthase β subunit gene in the rodent malaria parasite, Plasmodium berghei, ablating the protein that converts ADP to ATP. Disruption of the β subunit gene of the ATP synthase only marginally reduced asexual blood-stage parasite growth but completely blocked mouse-to-mouse transmission via Anopheles stephensi mosquitoes. Parasites lacking the β subunit gene of the ATP synthase generated viable gametes that fuse and form ookinetes but cannot progress beyond this stage. Ookinetes lacking the β subunit gene of the ATP synthase had normal motility but were not viable in the mosquito midgut and never made oocysts or sporozoites, thereby abrogating transmission to naive mice via mosquito bite. We crossed the self-infertile ATP synthase β subunit knockout parasites with a male-deficient, self-infertile strain of P. berghei, which restored fertility and production of oocysts and sporozoites, which demonstrates that mitochondrial ATP synthase is essential for ongoing viability through the female, mitochondrion-carrying line of sexual reproduction in P. berghei malaria. Perturbation of ATP synthase completely blocks transmission to the mosquito vector and could potentially be targeted for disease control.
authors.affiliation: Plant Cell Biology Research Centre, School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Angelika
authors.initials: A
authors.lastname: Sturm
authors.affiliation: Plant Cell Biology Research Centre, School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mollard
authors.affiliation: Plant Cell Biology Research Centre, School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Anton
authors.initials: A
authors.lastname: Cozijnsen
authors.affiliation: Plant Cell Biology Research Centre, School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: Plant Cell Biology Research Centre, School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia gim@unimelb.edu.au.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D019295:Computational Biology; D003433:Crosses, Genetic; D009033:Culicidae; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis; D008164:Luminescent Proteins / Q000378:metabolism; D008288:Malaria / Q000469:parasitology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D033661:Oocysts / Q000201:enzymology; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D010962:Plasmodium berghei / Q000201:enzymology* / Q000472:pathogenicity; D034101:Sporozoites / Q000201:enzymology; D019076:Transgenes
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases; D010100:Oxygen
keywords: ATP synthase; aerobic respiration; malaria; mitochondrial endosymbiosis; ookinetes
references.citation: J Biol Chem. 2005 Sep 9;280(36):31957-64
references.pmid: 15970588
references.citation: Mil Med. 1969 Sep;134(10):1074-80
references.pmid: 4316151
references.citation: FEMS Microbiol Rev. 2006 Jul;30(4):596-630
references.pmid: 16774588
references.citation: Nature. 2007 Mar 1;446(7131):88-91
references.pmid: 17330044
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):305-10
references.pmid: 18172196
references.citation: EMBO J. 2008 Apr 9;27(7):1154-60
references.pmid: 18323778
references.citation: J Cell Physiol. 2008 Dec;217(3):745-51
references.pmid: 18683212
references.citation: Eukaryot Cell. 2009 Jan;8(1):128-32
references.pmid: 18996983
references.citation: Annu Rev Microbiol. 2009;63:249-67
references.pmid: 19575561
references.citation: PLoS Pathog. 2009 Sep;5(9):e1000599
references.pmid: 19779564
references.citation: Curr Opin Microbiol. 2013 Aug;16(4):452-8
references.pmid: 23927894
references.citation: Cell Microbiol. 2014 May;16(5):734-50
references.pmid: 24612056
references.citation: PLoS Pathog. 2014 Jul;10(7):e1004263
references.pmid: 25032958
references.citation: J Eukaryot Microbiol. 2014 Nov-Dec;61(6):655-71
references.pmid: 25227912
references.citation: Cell. 2001 Jan 12;104(1):153-64
references.pmid: 11163248
references.citation: FEBS Lett. 2002 Aug 14;525(1-3):3-6
references.pmid: 12163151
references.citation: Nature. 2002 Oct 3;419(6906):498-511
references.pmid: 12368864
references.citation: Nature. 2002 Oct 3;419(6906):520-6
references.pmid: 12368866
references.citation: J Biomed Biotechnol. 2010;2010:976827
references.pmid: 20111746
references.citation: Ann Trop Med Parasitol. 1970 Jun;64(2):181-7
references.pmid: 4321621
references.citation: Proc R Soc Lond B Biol Sci. 1976 Mar 30;193(1110):55-76
references.pmid: 4810
references.citation: Eur J Biochem. 1982 Jul;125(3):471-7
references.pmid: 6214396
references.citation: J Biol Chem. 1983 Dec 25;258(24):15214-9
references.pmid: 6228552
references.citation: EMBO J. 1982;1(8):945-51
references.pmid: 6329717
references.citation: Curr Genet. 1993;23(4):360-4
references.pmid: 8467535
references.citation: Mol Biochem Parasitol. 1993 Jun;59(2):263-75
references.pmid: 8341324
references.citation: Mol Biochem Parasitol. 1993 Sep;61(1):59-68
references.pmid: 8259133
references.citation: Mol Biochem Parasitol. 1994 May;65(1):95-8
references.pmid: 7935632
references.citation: Am J Trop Med Hyg. 1964 Jul;13:515-9
references.pmid: 14196045
references.citation: Parasitology. 2004 Nov;129(Pt 5):511-24
references.pmid: 15552397
references.citation: Science. 2005 Jan 7;307(5706):82-6
references.pmid: 15637271
references.citation: Trends Parasitol. 2005 Jan;21(1):22-8
references.pmid: 15639737
references.citation: Pharmacogenomics. 2005 Jan;6(1):17-26
references.pmid: 15723602
references.citation: Cell. 2005 Jun 3;121(5):675-87
references.pmid: 15935755
references.citation: Mol Microbiol. 2005 Jul;57(2):405-19
references.pmid: 15978074
references.citation: Mitochondrion. 2009 Nov;9(6):443-53
references.pmid: 19682605
references.citation: Genome Biol. 2003;4(2):R9
references.pmid: 12620119
references.citation: Curr Mol Med. 2010 Feb;10(1):29-46
references.pmid: 20205678
references.citation: PLoS Pathog. 2010 Apr;6(4):e1000853
references.pmid: 20386715
references.citation: Mol Microbiol. 2010 Mar;75(6):1402-13
references.pmid: 20132450
references.citation: J Biol Chem. 2011 Sep 16;286(37):32661-71
references.pmid: 21771793
references.citation: Annu Rev Cell Dev Biol. 2011;27:441-64
references.pmid: 21985671
references.citation: J Biol Chem. 2011 Dec 2;286(48):41312-22
references.pmid: 21984828
references.citation: Int J Parasitol. 2012;42(3):249-58
references.pmid: 22366731
references.citation: J Cell Sci. 2012 Apr 15;125(Pt 8):2053-63
references.pmid: 22328505
references.citation: Microbiol Mol Biol Rev. 2012 Jun;76(2):444-95
references.pmid: 22688819
references.citation: J Biochem. 2012 Sep;152(3):259-68
references.pmid: 22628552
references.citation: Biochem Soc Trans. 2013 Feb 1;41(1):1-16
references.pmid: 23356252
references.citation: BMC Biol. 2013;11:67
references.pmid: 23763941
references.citation: Mol Biochem Parasitol. 2003 Dec;132(2):59-66
references.pmid: 14599665
references.citation: Mol Biochem Parasitol. 2004 Sep;137(1):23-33
references.pmid: 15279948
references.citation: J Ultrastruct Res. 1969 Feb;26(3):316-31
references.pmid: 4887539
references.citation: Exp Parasitol. 1969 Aug;25(1):181-92
references.pmid: 5362580
references.citation: FEBS Lett. 2005 Oct 24;579(25):5769-72
references.pmid: 16223490