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+Targeting Mitochondrial Functions as Antimalarial Regime, What Is Next?

  • Parasitology (N Kumar, Section Editor)
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Abstract

Purpose of Review

Malaria parasites continue to demonstrate their ability to evolve drug resistance, underscoring the need to maintain a long-term program of antimalarial drug development. The parasite mitochondrion is an essential organelle in every lifecycle stage. In the parasite, there are ~ 300 proteins encoded on the nuclear genome destined for the mitochondrion (around 6% of the genome), plus 3 protein genes present on the 6-kb mitochondrial genome. Many of these gene products compose pathways that are critical for the mitochondrion and the mitochondrial contribution to the parasite. The mitochondrial electron transport chain (mtETC) is essential for the parasite and has been validated as an antimalarial drug target. Another mitochondrially located target is the parasite dihydroorotate dehydrogenase (DHODH), which is involved in the essential pyrimidine biosynthesis pathway. In this review, we will summarize recent advancements in drug development targeting the mtETC and DHODH. We will also discuss other pathways within the mitochondrion that hold promise for future exploitation in the search for additional antimalarial drug targets.

Recent Findings

Recent drug development efforts have advanced two compounds into clinical evaluation, ELQ-300 and DSM265, targeting the mtETC and DHODH, respectively. These compounds are very potent against malaria parasites at multiple lifecycle stages and have shown good pharmacological properties such as long half-lives and metabolic stability. However, progress toward the development of antimalarial compounds against other mitochondrial functions has been very limited.

Summary

New drugs that target the mtETC and DHODH are likely to reach the clinic in the near future. Additional studies are required to verify the essentiality of other mitochondrial pathways in malaria parasites and validate novel antimalarial drug targets needed to help ensure the continuing future development of new antimalarial drugs.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Martin WF, Neukirchen S, Zimorski V, Gould SB, Sousa FL. Energy for two: new archaeal lineages and the origin of mitochondria. BioEssays. 2016;38(9):850–6. https://doi.org/10.1002/bies.201600089.

    Article  PubMed  Google Scholar 

  2. Pittis AA, Gabaldon T. Late acquisition of mitochondria by a host with chimaeric prokaryotic ancestry. Nature. 2016;531(7592):101–4. https://doi.org/10.1038/nature16941.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Gray MW. The pre-endosymbiont hypothesis: a new perspective on the origin and evolution of mitochondria. Cold Spring Harb Perspect Biol. 2014;6(3). doi:https://doi.org/10.1101/cshperspect.a016097.

  4. Adl SM, Leander BS, Simpson AG, Archibald JM, Anderson OR, Bass D, et al. Diversity, nomenclature, and taxonomy of protists. Syst Biol. 2007;56(4):684–9. https://doi.org/10.1080/10635150701494127.

    Article  PubMed  Google Scholar 

  5. Poinar G Jr. Plasmodium dominicana n. sp. (Plasmodiidae: Haemospororida) from Tertiary Dominican amber. Syst Parasitol. 2005;61(1):47–52. https://doi.org/10.1007/s11230-004-6354-6.

    Article  PubMed  Google Scholar 

  6. WHO: World Malaria Report. 2016. http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/.

  7. Vaidya AB, Arasu P. Tandemly arranged gene clusters of malarial parasites that are highly conserved and transcribed. Mol Biochem Parasitol. 1987;22(2–3):249–57.

    Article  CAS  PubMed  Google Scholar 

  8. Vaidya AB, Akella R, Suplick K. Sequences similar to genes for two mitochondrial proteins and portions of ribosomal RNA in tandemly arrayed 6-kilobase-pair DNA of a malarial parasite. Mol Biochem Parasitol. 1989;35(2):97–107.

    Article  CAS  PubMed  Google Scholar 

  9. Vaidya AB. Mitochondrial and plastid functions as antimalarial drug targets. Curr Drug Targets Infect Disord. 2004;4(1):11–23.

    Article  CAS  PubMed  Google Scholar 

  10. Vaidya AB, Mather MWA. Post-genomic view of the mitochondrion in malaria parasites. Curr Top Microbiol Immunol. 2005;295:233–50.

    CAS  PubMed  Google Scholar 

  11. Mather MW, Vaidya AB. Mitochondria in malaria and related parasites: ancient, diverse and streamlined. J Bioenerg Biomembr. 2008;40(5):425–33. https://doi.org/10.1007/s10863-008-9176-4.

    Article  CAS  PubMed  Google Scholar 

  12. Vaidya AB, Mather MW. Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol. 2009;63:249–67. https://doi.org/10.1146/annurev.micro.091208.073424.

    Article  CAS  PubMed  Google Scholar 

  13. Sheiner L, Vaidya AB, McFadden GI. The metabolic roles of the endosymbiotic organelles of Toxoplasma and Plasmodium spp. Curr Opin Microbiol. 2013;16(4):452–8. https://doi.org/10.1016/j.mib.2013.07.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hikosaka K, Kita K, Tanabe K. Diversity of mitochondrial genome structure in the phylum Apicomplexa. Mol Biochem Parasitol. 2013;188(1):26–33. https://doi.org/10.1016/j.molbiopara.2013.02.006.

    Article  CAS  PubMed  Google Scholar 

  15. Jacot D, Waller RF, Soldati-Favre D, MacPherson DA, MacRae JI. Apicomplexan energy metabolism: carbon source promiscuity and the quiescence hyperbole. Trends Parasitol. 2016;32(1):56–70. https://doi.org/10.1016/j.pt.2015.09.001.

    Article  CAS  PubMed  Google Scholar 

  16. Sherman IW. Biochemistry of Plasmodium (malarial parasites). Microbiol Rev. 1979;43(4):453–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Balabaskaran Nina P, Morrisey JM, Ganesan SM, Ke H, Pershing AM, Mather MW, et al. ATP synthase complex of Plasmodium falciparum: dimeric assembly in mitochondrial membranes and resistance to genetic disruption. J Biol Chem. 2011;286(48):41312–22. https://doi.org/10.1074/jbc.M111.290973.

    Article  PubMed  CAS  Google Scholar 

  18. Sturm A, Mollard V, Cozijnsen A, Goodman CD, McFadden GI. Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase. Proc Natl Acad Sci U S A. 2015;112(33):10216–23. https://doi.org/10.1073/pnas.1423959112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Balabaskaran Nina P, Dudkina NV, Kane LA, van Eyk JE, Boekema EJ, Mather MW, et al. Highly divergent mitochondrial ATP synthase complexes in Tetrahymena thermophila. PLoS Biol. 2010;8(7):e1000418. https://doi.org/10.1371/journal.pbio.1000418.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Gutteridge WE, Dave D, Richards WH. Conversion of dihydroorotate to orotate in parasitic protozoa. Biochim Biophys Acta. 1979;582(3):390–401.

    Article  CAS  PubMed  Google Scholar 

  21. Painter HJ, Morrisey JM, Mather MW, Vaidya AB. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature. 2007;446(7131):88–91. https://doi.org/10.1038/nature05572.

    Article  CAS  PubMed  Google Scholar 

  22. Phillips MA, Rathod PK. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets. 2010;10(3):226–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rodrigues T, Lopes F, Moreira R. Inhibitors of the mitochondrial electron transport chain and de novo pyrimidine biosynthesis as antimalarials: the present status. Curr Med Chem. 2010;17(10):929–56.

    Article  CAS  PubMed  Google Scholar 

  24. Nixon GL, Pidathala C, Shone AE, Antoine T, Fisher N, O'Neill PM, et al. Targeting the mitochondrial electron transport chain of Plasmodium falciparum: new strategies towards the development of improved antimalarials for the elimination era. Future Med Chem. 2013;5(13):1573–91. https://doi.org/10.4155/fmc.13.121.

    Article  CAS  PubMed  Google Scholar 

  25. Stocks PA, Barton V, Antoine T, Biagini GA, Ward SA, O'Neill PM. Novel inhibitors of the Plasmodium falciparum electron transport chain. Parasitology. 2014;141(1):50–65. https://doi.org/10.1017/S0031182013001571.

    Article  CAS  PubMed  Google Scholar 

  26. Mitchell P. The protonmotive Q cycle: a general formulation. FEBS Lett. 1975;59(2):137–9.

    Article  CAS  PubMed  Google Scholar 

  27. Vaidya AB, Lashgari MS, Pologe LG, Morrisey J. Structural features of Plasmodium cytochrome b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones. Mol Biochem Parasitol. 1993;58(1):33–42.

    Article  CAS  PubMed  Google Scholar 

  28. Fieser LF, Heymann H. Naphthoquinone antimalarials; relative antirespiratory activities (Plasmodium lophurae). J Biol Chem. 1948;176(3):1363–70.

    CAS  PubMed  Google Scholar 

  29. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol. 1992;43(7):1545–53.

    Article  CAS  PubMed  Google Scholar 

  30. Chiodini PL, Conlon CP, Hutchinson DB, Farquhar JA, Hall AP, Peto TE, et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother. 1995;36(6):1073–8.

    Article  CAS  PubMed  Google Scholar 

  31. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg. 1996;54(1):62–6.

    Article  CAS  PubMed  Google Scholar 

  32. Canfield CJ, Pudney M, Gutteridge WE. Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro. Exp Parasitol. 1995;80(3):373–81. https://doi.org/10.1006/expr.1995.1049.

    Article  CAS  PubMed  Google Scholar 

  33. Markley LD, Van Heertum JC, Doorenbos HE. Antimalarial activity of clopidol, 3,5-dichloro-2,6-dimethyl-4-pyridinol, and its esters, carbonates, and sulfonates. J Med Chem. 1972;15(11):1188–9.

    Article  CAS  PubMed  Google Scholar 

  34. Xiang H, McSurdy-Freed J, Moorthy GS, Hugger E, Bambal R, Han C, et al. Preclinical drug metabolism and pharmacokinetic evaluation of GW844520, a novel anti-malarial mitochondrial electron transport inhibitor. J Pharm Sci. 2006;95(12):2657–72. https://doi.org/10.1002/jps.20681.

    Article  CAS  PubMed  Google Scholar 

  35. Bueno JM, Herreros E, Angulo-Barturen I, Ferrer S, Fiandor JM, Gamo FJ, et al. Exploration of 4(1H)-pyridones as a novel family of potent antimalarial inhibitors of the plasmodial cytochrome bc1. Future Med Chem. 2012;4(18):2311–23. https://doi.org/10.4155/fmc.12.177.

    Article  CAS  PubMed  Google Scholar 

  36. Yeates CL, Batchelor JF, Capon EC, Cheesman NJ, Fry M, Hudson AT, et al. Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials. J Med Chem. 2008;51(9):2845–52. https://doi.org/10.1021/jm0705760.

    Article  CAS  PubMed  Google Scholar 

  37. Capper MJ, O'Neill PM, Fisher N, Strange RW, Moss D, Ward SA, et al. Antimalarial 4(1H)-pyridones bind to the qi site of cytochrome bc1. Proc Natl Acad Sci U S A. 2015;112(3):755–60. https://doi.org/10.1073/pnas.1416611112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Monastyrskyi A, Kyle DE, Manetsch R. 4(1H)-pyridone and 4(1H)-quinolone derivatives as antimalarials with erythrocytic, exoerythrocytic, and transmission blocking activities. Curr Top Med Chem. 2014;14(14):1693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. •• Nilsen A, LaCrue AN, White KL, Forquer IP, Cross RM, Marfurt J, et al. Quinolone-3-diarylethers: a new class of antimalarial drug. Sci Transl Med. 2013;5(177):177ra37. https://doi.org/10.1126/scitranslmed.3005029. The preclinical candidate ELQ-300 is a novel bc 1 complex inhibitor with high potency and multi-stage antimalarial activity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Nilsen A, Miley GP, Forquer IP, Mather MW, Katneni K, Li Y, et al. Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. J Med Chem. 2014;57(9):3818–34. https://doi.org/10.1021/jm500147k.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Miley GP, Pou S, Winter R, Nilsen A, Li Y, Kelly JX, et al. ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. Antimicrob Agents Chemother. 2015;59(9):5555–60. https://doi.org/10.1128/AAC.01183-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stickles AM, de Almeida MJ, Morrisey JM, Sheridan KA, Forquer IP, Nilsen A, et al. Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum. Antimicrob Agents Chemother. 2015;59(4):1977–82. https://doi.org/10.1128/AAC.04149-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stickles AM, Smilkstein MJ, Morrisey JM, Li Y, Forquer IP, Kelly JX, et al. Atovaquone and ELQ-300 combination therapy as a novel dual-site cytochrome bc1 inhibition strategy for malaria. Antimicrob Agents Chemother. 2016;60(8):4853–9. https://doi.org/10.1128/AAC.00791-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Biagini GA, Fisher N, Berry N, Stocks PA, Meunier B, Williams DP, et al. Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Mol Pharmacol. 2008;73(5):1347–55. https://doi.org/10.1124/mol.108.045120.

    Article  CAS  PubMed  Google Scholar 

  45. Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Bagby GC, Rathbun RK, et al. Evaluation and lead optimization of anti-malarial acridones. Exp Parasitol. 2006;114(1):47–56. https://doi.org/10.1016/j.exppara.2006.03.014.

    Article  CAS  PubMed  Google Scholar 

  46. Kelly JX, Smilkstein MJ, Cooper RA, Lane KD, Johnson RA, Janowsky A, et al. Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum. Antimicrob Agents Chemother. 2007;51(11):4133–40. https://doi.org/10.1128/AAC.00669-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kelly JX, Smilkstein MJ, Brun R, Wittlin S, Cooper RA, Lane KD, et al. Discovery of dual function acridones as a new antimalarial chemotype. Nature. 2009;459(7244):270–3. https://doi.org/10.1038/nature07937.

    Article  CAS  PubMed  Google Scholar 

  48. Cross RM, Maignan JR, Mutka TS, Luong L, Sargent J, Kyle DE, et al. Optimization of 1,2,3,4-tetrahydroacridin-9(10H)-ones as antimalarials utilizing structure-activity and structure-property relationships. J Med Chem. 2011;54(13):4399–426. https://doi.org/10.1021/jm200015a.

    Article  CAS  PubMed  Google Scholar 

  49. Valdes AF. Acridine and acridinones: old and new structures with antimalarial activity. Open Med Chem J. 2011;5:11–20. https://doi.org/10.2174/1874104501105010011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vyas VK, Ghate M. Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini Rev Med Chem. 2011;11(12):1039–55.

    Article  CAS  PubMed  Google Scholar 

  51. Baldwin J, Michnoff CH, Malmquist NA, White J, Roth MG, Rathod PK, et al. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem. 2005;280(23):21847–53. https://doi.org/10.1074/jbc.M501100200.

    Article  CAS  PubMed  Google Scholar 

  52. Phillips MA, Gujjar R, Malmquist NA, White J, El Mazouni F, Baldwin J, et al. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. J Med Chem. 2008;51(12):3649–53. https://doi.org/10.1021/jm8001026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gujjar R, Marwaha A, El Mazouni F, White J, White KL, Creason S, et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem. 2009;52(7):1864–72. https://doi.org/10.1021/jm801343r.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gujjar R, El Mazouni F, White KL, White J, Creason S, Shackleford DM, et al. Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J Med Chem. 2011;54(11):3935–49. https://doi.org/10.1021/jm200265b.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, et al. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem. 2011;54(15):5540–61. https://doi.org/10.1021/jm200592f.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. •• Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med. 2015;7(296):296ra111. https://doi.org/10.1126/scitranslmed.aaa6645. DSM265 is the first PfDHODH inhibitor to reach clinical development. It is highly effective against malaria parasites at multiple stages.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Pavadai E, El Mazouni F, Wittlin S, de Kock C, Phillips MA, Chibale K. Identification of new human malaria parasite Plasmodium falciparum dihydroorotate dehydrogenase inhibitors by pharmacophore and structure-based virtual screening. J Chem Inf Model. 2016;56(3):548–62. https://doi.org/10.1021/acs.jcim.5b00680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kokkonda S, Deng X, White KL, Coteron JM, Marco M, de Las Heras L, et al. Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity. J Med Chem. 2016;59(11):5416–31. https://doi.org/10.1021/acs.jmedchem.6b00275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Patel V, Booker M, Kramer M, Ross L, Celatka CA, Kennedy LM, et al. Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem. 2008;283(50):35078–85. https://doi.org/10.1074/jbc.M804990200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Booker ML, Bastos CM, Kramer ML, Barker RH Jr, Skerlj R, Sidhu AB, et al. Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem. 2010;285(43):33054–64. https://doi.org/10.1074/jbc.M110.162081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Skerlj RT, Bastos CM, Booker ML, Kramer ML, Barker RH, Jr., Celatka CA et al. Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria. ACS Med Chem Lett 2011;2(9):708–713. doi:https://doi.org/10.1021/ml200143c.

  62. Deng X, Gujjar R, El Mazouni F, Kaminsky W, Malmquist NA, Goldsmith EJ, et al. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem. 2009;284(39):26999–7009. https://doi.org/10.1074/jbc.M109.028589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu M, Zhu J, Diao Y, Zhou H, Ren X, Sun D, et al. Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives. J Med Chem. 2013;56(20):7911–24. https://doi.org/10.1021/jm400938g.

    Article  CAS  PubMed  Google Scholar 

  64. Nam TG, McNamara CW, Bopp S, Dharia NV, Meister S, Bonamy GM, et al. A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chem Biol. 2011;6(11):1214–22. https://doi.org/10.1021/cb200105d.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, et al. Chemical genetics of Plasmodium falciparum. Nature. 2010;465(7296):311–5. https://doi.org/10.1038/nature09099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ke H, Morrisey JM, Ganesan SM, Painter HJ, Mather MW, Vaidya AB. Variation among Plasmodium falciparum strains in their reliance on mitochondrial electron transport chain function. Eukaryot Cell. 2011;10(8):1053–61. https://doi.org/10.1128/EC.05049-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Biagini GA, Fisher N, Shone AE, Mubaraki MA, Srivastava A, Hill A, et al. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc Natl Acad Sci U S A. 2012;109(21):8298–303. https://doi.org/10.1073/pnas.1205651109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Boysen KE, Matuschewski K. Arrested oocyst maturation in Plasmodium parasites lacking type II NADH:ubiquinone dehydrogenase. J Biol Chem. 2011;286(37):32661–71. https://doi.org/10.1074/jbc.M111.269399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. •• Goodman CD, Siregar JE, Mollard V, Vega-Rodriguez J, Syafruddin D, Matsuoka H, et al. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science. 2016;352(6283):349–53. https://doi.org/10.1126/science.aad9279. This study confirmed that there is a fitness cost associated with drug resistance. Atovaquone resistant parasites are not transmitted by mosquitoes, suggesting that atovaquone or other drugs that target pathways important for the parasite insect stage may be useful to help prevent the spread of resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mather MW, Darrouzet E, Valkova-Valchanova M, Cooley JW, McIntosh MT, Daldal F, et al. Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. J Biol Chem. 2005;280(29):27458–65. https://doi.org/10.1074/jbc.M502319200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fisher N, Abd Majid R, Antoine T, Al-Helal M, Warman AJ, Johnson DJ, et al. Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression. J Biol Chem. 2012;287(13):9731–41. https://doi.org/10.1074/jbc.M111.324319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ke H, Lewis IA, Morrisey JM, McLean KJ, Ganesan SM, Painter HJ, et al. Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle. Cell Rep. 2015;11(1):164–74. https://doi.org/10.1016/j.celrep.2015.03.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hino A, Hirai M, Tanaka TQ, Watanabe Y, Matsuoka H, Kita K. Critical roles of the mitochondrial complex II in oocyst formation of rodent malaria parasite Plasmodium berghei. J Biochem. 2012;152(3):259–68. https://doi.org/10.1093/jb/mvs058.

    Article  CAS  PubMed  Google Scholar 

  74. Tanaka TQ, Hirai M, Watanabe Y, Kita K. Toward understanding the role of mitochondrial complex II in the intraerythrocytic stages of Plasmodium falciparum: gene targeting of the Fp subunit. Parasitol Int. 2012;61(4):726–8. https://doi.org/10.1016/j.parint.2012.06.002.

    Article  CAS  PubMed  Google Scholar 

  75. Guler JL, Freeman DL, Ahyong V, Patrapuvich R, White J, Gujjar R, et al. Asexual populations of the human malaria parasite, Plasmodium falciparum, use a two-step genomic strategy to acquire accurate, beneficial DNA amplifications. PLoS Pathog. 2013;9(5):e1003375. https://doi.org/10.1371/journal.ppat.1003375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gonczarowska-Jorge H, Zahedi RP, Sickmann A. The proteome of baker’s yeast mitochondria. Mitochondrion. 2016 https://doi.org/10.1016/j.mito.2016.08.007.

  77. Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2016;44(D1):D1251–7. https://doi.org/10.1093/nar/gkv1003.

    Article  CAS  PubMed  Google Scholar 

  78. Surolia N, Padmanaban G. De novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Biochem Biophys Res Commun. 1992;187(2):744–50.

    Article  CAS  PubMed  Google Scholar 

  79. Padmanaban G, Rangarajan PN. Heme metabolism of Plasmodium is a major antimalarial target. Biochem Biophys Res Commun. 2000;268(3):665–8. https://doi.org/10.1006/bbrc.1999.1892.

    Article  CAS  PubMed  Google Scholar 

  80. Padmanaban G, Nagaraj VA, Rangarajan PN. An alternative model for heme biosynthesis in the malarial parasite. Trends Biochem Sci. 2007;32(10):443–9. https://doi.org/10.1016/j.tibs.2007.09.005.

    Article  CAS  PubMed  Google Scholar 

  81. Padmanaban G, Rangarajan PN. Emerging targets for antimalarial drugs. Expert Opin Ther Targets. 2001;5(4):423–41. https://doi.org/10.1517/14728222.5.4.423.

    Article  CAS  PubMed  Google Scholar 

  82. van Dooren GG, Kennedy AT, McFadden GI. The use and abuse of heme in apicomplexan parasites. Antioxid Redox Signal. 2012;17(4):634–56. https://doi.org/10.1089/ars.2012.4539.

    Article  PubMed  CAS  Google Scholar 

  83. Ke H, Sigala PA, Miura K, Morrisey JM, Mather MW, Crowley JR, et al. The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages. J Biol Chem. 2014;289(50):34827–37. https://doi.org/10.1074/jbc.M114.615831.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Nagaraj VA, Sundaram B, Varadarajan NM, Subramani PA, Kalappa DM, Ghosh SK, et al. Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection. PLoS Pathog. 2013;9(8):e1003522. https://doi.org/10.1371/journal.ppat.1003522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. MacRae JI, Dixon MW, Dearnley MK, Chua HH, Chambers JM, Kenny S, et al. Mitochondrial metabolism of sexual and asexual blood stages of the malaria parasite Plasmodium falciparum. BMC Biol. 2013;11:67. https://doi.org/10.1186/1741-7007-11-67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Cobbold SA, Vaughan AM, Lewis IA, Painter HJ, Camargo N, Perlman DH, et al. Kinetic flux profiling elucidates two independent acetyl-CoA biosynthetic pathways in Plasmodium falciparum. J Biol Chem. 2013;288(51):36338–50. https://doi.org/10.1074/jbc.M113.503557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Storm J, Sethia S, Blackburn GJ, Chokkathukalam A, Watson DG, Breitling R, et al. Phosphoenolpyruvate carboxylase identified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism. PLoS Pathog. 2014;10(1):e1003876. https://doi.org/10.1371/journal.ppat.1003876.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Foth BJ, Stimmler LM, Handman E, Crabb BS, Hodder AN, McFadden GI. The malaria parasite Plasmodium falciparum has only one pyruvate dehydrogenase complex, which is located in the apicoplast. Mol Microbiol. 2005;55(1):39–53. https://doi.org/10.1111/j.1365-2958.2004.04407.x.

    Article  CAS  PubMed  Google Scholar 

  89. Oppenheim RD, Creek DJ, Macrae JI, Modrzynska KK, Pino P, Limenitakis J, et al. BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei. PLoS Pathog. 2014;10(7):e1004263. https://doi.org/10.1371/journal.ppat.1004263.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Bulusu V, Jayaraman V, Balaram H. Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum. J Biol Chem. 2011;286(11):9236–45. https://doi.org/10.1074/jbc.M110.173328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bulusu V, Srinivasan B, Bopanna MP, Balaram H. Elucidation of the substrate specificity, kinetic and catalytic mechanism of adenylosuccinate lyase from Plasmodium falciparum. Biochim Biophys Acta. 2009;1794(4):642–54. https://doi.org/10.1016/j.bbapap.2008.11.021.

    Article  CAS  PubMed  Google Scholar 

  92. Woods SA, Schwartzbach SD, Guest JR. Two biochemically distinct classes of fumarase in Escherichia coli. Biochim Biophys Acta. 1988;954(1):14–26.

    Article  CAS  PubMed  Google Scholar 

  93. Flint DH, Emptage MH, Guest JR. Fumarase a from Escherichia coli: purification and characterization as an iron-sulfur cluster containing enzyme. Biochemistry. 1992;31(42):10331–7.

    Article  CAS  PubMed  Google Scholar 

  94. van Dooren GG, Stimmler LM, McFadden GI. Metabolic maps and functions of the Plasmodium mitochondrion. FEMS Microbiol Rev. 2006;30(4):596–630. https://doi.org/10.1111/j.1574-6976.2006.00027.x.

    Article  PubMed  CAS  Google Scholar 

  95. Prommana P, Uthaipibull C, Wongsombat C, Kamchonwongpaisan S, Yuthavong Y, Knuepfer E, et al. Inducible knockdown of Plasmodium gene expression using the glmS ribozyme. PLoS One. 2013;8(8):e73783. https://doi.org/10.1371/journal.pone.0073783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ganesan SM, Falla A, Goldfless SJ, Nasamu AS, Niles JC. Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites. Nat Commun. 2016;7:10727. https://doi.org/10.1038/ncomms10727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Preiser PR, Wilson RJ, Moore PW, McCready S, Hajibagheri MA, Blight KJ, et al. Recombination associated with replication of malarial mitochondrial DNA. EMBO J. 1996;15(3):684–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ji YE, Mericle BL, Rehkopf DH, Anderson JD, Feagin JE. The Plasmodium falciparum 6 kb element is polycistronically transcribed. Mol Biochem Parasitol. 1996;81(2):211–23.

    Article  PubMed  Google Scholar 

  99. Suplick K, Morrisey J, Vaidya AB. Complex transcription from the extrachromosomal DNA encoding mitochondrial functions of Plasmodium yoelii. Mol Cell Biol. 1990;10(12):6381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ke H, Morrisey JM, Ganesan SM, Mather MW, Vaidya AB. Mitochondrial RNA polymerase is an essential enzyme in erythrocytic stages of Plasmodium falciparum. Mol Biochem Parasitol. 2012;185(1):48–51. https://doi.org/10.1016/j.molbiopara.2012.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gupta A, Shah P, Haider A, Gupta K, Siddiqi MI, Ralph SA, et al. Reduced ribosomes of the apicoplast and mitochondrion of Plasmodium spp. and predicted interactions with antibiotics. Open Biol. 2014;4(5):140045. https://doi.org/10.1098/rsob.140045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Greber BJ, Boehringer D, Leitner A, Bieri P, Voigts-Hoffmann F, Erzberger JP, et al. Architecture of the large subunit of the mammalian mitochondrial ribosome. Nature. 2014;505(7484):515–9. https://doi.org/10.1038/nature12890.

    Article  CAS  PubMed  Google Scholar 

  103. Kaushal PS, Sharma MR, Booth TM, Haque EM, Tung CS, Sanbonmatsu KY, et al. Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. Proc Natl Acad Sci U S A. 2014;111(20):7284–9. https://doi.org/10.1073/pnas.1401657111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zikova A, Panigrahi AK, Dalley RA, Acestor N, Anupama A, Ogata Y, et al. Trypanosoma brucei mitochondrial ribosomes: affinity purification and component identification by mass spectrometry. Mol Cell Proteomics. 2008;7(7):1286–96. https://doi.org/10.1074/mcp.M700490-MCP200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Feagin JE, Harrell MI, Lee JC, Coe KJ, Sands BH, Cannone JJ, et al. The fragmented mitochondrial ribosomal RNAs of Plasmodium falciparum. PLoS One. 2012;7(6):e38320. https://doi.org/10.1371/journal.pone.0038320.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Haider A, Allen SM, Jackson KE, Ralph SA, Habib S. Targeting and function of proteins mediating translation initiation in organelles of Plasmodium falciparum. Mol Microbiol. 2015;96(4):796–814. https://doi.org/10.1111/mmi.12972.

    Article  CAS  PubMed  Google Scholar 

  107. Gupta A, Mir SS, Saqib U, Biswas S, Vaishya S, Srivastava K, et al. The effect of fusidic acid on Plasmodium falciparum elongation factor G (EF-G). Mol Biochem Parasitol. 2013;192(1–2):39–48. https://doi.org/10.1016/j.molbiopara.2013.10.003.

    Article  CAS  PubMed  Google Scholar 

  108. Vaishya S, Kumar V, Gupta A, Siddiqi MI, Habib S. Polypeptide release factors and stop codon recognition in the apicoplast and mitochondrion of Plasmodium falciparum. Mol Microbiol. 2016;100(6):1080–95. https://doi.org/10.1111/mmi.13369.

    Article  CAS  PubMed  Google Scholar 

  109. Gupta A, Mir SS, Jackson KE, Lim EE, Shah P, Sinha A, et al. Recycling factors for ribosome disassembly in the apicoplast and mitochondrion of Plasmodium falciparum. Mol Microbiol. 2013;88(5):891–905. https://doi.org/10.1111/mmi.12230.

    Article  CAS  PubMed  Google Scholar 

  110. Habib S, Vaishya S, Gupta K. Translation in organelles of apicomplexan parasites. Trends Parasitol. 2016. doi:https://doi.org/10.1016/j.pt.2016.07.005.

  111. Kessl JJ, Lange BB, Merbitz-Zahradnik T, Zwicker K, Hill P, Meunier B, et al. Molecular basis for atovaquone binding to the cytochrome bc1 complex. J Biol Chem. 2003;278(33):31312–8. https://doi.org/10.1074/jbc.M304042200.

    Article  CAS  PubMed  Google Scholar 

  112. Beinert H. Iron-sulfur proteins: ancient structures, still full of surprises. J Biol Inorg Chem. 2000;5(1):2–15.

    Article  CAS  PubMed  Google Scholar 

  113. Beinert H, Holm RH, Munck E. Iron-sulfur clusters: nature’s modular, multipurpose structures. Science. 1997;277(5326):653–9.

    Article  CAS  PubMed  Google Scholar 

  114. Tachezy J, Sanchez LB, Muller M. Mitochondrial type iron-sulfur cluster assembly in the amitochondriate eukaryotes Trichomonas vaginalis and Giardia intestinalis, as indicated by the phylogeny of IscS. Mol Biol Evol. 2001;18(10):1919–28.

    Article  CAS  PubMed  Google Scholar 

  115. • Karnkowska A, Vacek V, Zubacova Z, Treitli SC, Petrzelkova R, Eme L, et al. A eukaryote without a mitochondrial organelle. Curr Biol. 2016;26(10):1274–84. https://doi.org/10.1016/j.cub.2016.03.053. This study discovered the first eukaryote, Monocercomonoides sp , without a mitochondrion or a mitochondrion derivative organelle. The essential mitochondrial iron-sulfur cluster biosynthesis pathway is replaced by a cytosolic pathway encoded by bacterial genes acquired through lateral gene transfer.

    Article  CAS  PubMed  Google Scholar 

  116. Mather MW, Henry KW, Vaidya AB. Mitochondrial drug targets in apicomplexan parasites. Curr Drug Targets. 2007;8(1):49–60.

    Article  CAS  PubMed  Google Scholar 

  117. Stehling O, Wilbrecht C, Lill R. Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie. 2014;100:61–77. https://doi.org/10.1016/j.biochi.2014.01.010.

    Article  CAS  PubMed  Google Scholar 

  118. Gisselberg JE, Dellibovi-Ragheb TA, Matthews KA, Bosch G, Prigge ST. The suf iron-sulfur cluster synthesis pathway is required for apicoplast maintenance in malaria parasites. PLoS Pathog. 2013;9(9):e1003655. https://doi.org/10.1371/journal.ppat.1003655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nyakundi DO, Vuko LA, Bentley SJ, Hoppe H, Blatch GL, Boshoff A. Plasmodium falciparum Hep1 is required to prevent the self aggregation of PfHsp70-3. PLoS One. 2016;11(6):e0156446. https://doi.org/10.1371/journal.pone.0156446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Bhaduri-McIntosh S, Vaidya AB. Molecular characterization of a Plasmodium falciparum gene encoding the mitochondrial phosphate carrier. Mol Biochem Parasitol. 1996;78(1–2):297–301.

    Article  CAS  PubMed  Google Scholar 

  121. Bhaduri-McIntosh S, Vaidya AB. Plasmodium falciparum: import of a phosphate carrier protein into heterologous mitochondria. Exp Parasitol. 1998;88(3):252–4. https://doi.org/10.1006/expr.1998.4242.

    Article  CAS  PubMed  Google Scholar 

  122. Hatin I, Jambou R, Ginsburg H, Jaureguiberry G. Single or multiple localization of ADP/ATP transporter in human malarial Plasmodium falciparum. Biochem Pharmacol. 1992;43(1):71–5.

    Article  CAS  PubMed  Google Scholar 

  123. Hatin I, Jaureguiberry G. Molecular characterisation of the ADP/ATP-transporter cDNA from the human malaria parasite Plasmodium falciparum. Eur J Biochem. 1995;228(1):86–91.

    Article  CAS  PubMed  Google Scholar 

  124. Jambou R, Hatin I, Jaureguiberry G. Evidence by in situ hybridization for stage-specific expression of the ATP/ADP translocator mRNA in Plasmodium falciparum. Exp Parasitol. 1995;80(3):568–71. https://doi.org/10.1006/expr.1995.1070.

    Article  CAS  PubMed  Google Scholar 

  125. Nozawa A, Fujimoto R, Matsuoka H, Tsuboi T, Tozawa Y. Cell-free synthesis, reconstitution, and characterization of a mitochondrial dicarboxylate-tricarboxylate carrier of Plasmodium falciparum. Biochem Biophys Res Commun. 2011;414(3):612–7. https://doi.org/10.1016/j.bbrc.2011.09.130.

    Article  CAS  PubMed  Google Scholar 

  126. Pino P, Aeby E, Foth BJ, Sheiner L, Soldati T, Schneider A, et al. Mitochondrial translation in absence of local tRNA aminoacylation and methionyl tRNA Met formylation in Apicomplexa. Mol Microbiol. 2010;76(3):706–18. https://doi.org/10.1111/j.1365-2958.2010.07128.x.

    Article  CAS  PubMed  Google Scholar 

  127. Sharma A, Sharma A. Plasmodium falciparum mitochondria import tRNAs along with an active phenylalanyl-tRNA synthetase. Biochem J. 2015;465(3):459–69. https://doi.org/10.1042/BJ20140998.

    Article  CAS  PubMed  Google Scholar 

  128. Tonhosolo R, D'Alexandri FL, Genta FA, Wunderlich G, Gozzo FC, Eberlin MN, et al. Identification, molecular cloning and functional characterization of an octaprenyl pyrophosphate synthase in intra-erythrocytic stages of Plasmodium falciparum. Biochem J. 2005;392(Pt 1):117–26. https://doi.org/10.1042/BJ20050441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tonhosolo R, D’Alexandri FL, de Rosso VV, Gazarini ML, Matsumura MY, Peres VJ, et al. Carotenoid biosynthesis in intraerythrocytic stages of Plasmodium falciparum. J Biol Chem. 2009;284(15):9974–85. https://doi.org/10.1074/jbc.M807464200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jenkins BJ, Daly TM, Morrisey JM, Mather MW, Vaidya AB, Bergman LW. Characterization of a plasmodium falciparum orthologue of the yeast ubiquinone-binding protein, Coq10p. PLoS One. 2016;11(3):e0152197. https://doi.org/10.1371/journal.pone.0152197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. •• Sidik SM, Huet D, Ganesan SM, Huynh MH, Wang T, Nasamu AS, et al. A genome-wide CRISPR screen in Toxoplasma identifies essential apicomplexan genes. Cell. 2016;166(6):1423–35 e12. https://doi.org/10.1016/j.cell.2016.08.019. This is the first genome-wide knockout screening carried out by a CRISPR-Cas9 system in an apicomplexan parasite. The feasibility of CRISPR-Cas9 knockout in Toxoplasma allowed the discovery of essential genes that were not previously characterized, termed “indispensable conserved apicomplexan proteins” (ICAP). Studies on these ICAP genes may identify novel essential pathways of apicomplexan parasites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our colleagues at the Center for Parasitology at Drexel University College of Medicine for comments and advice.

Funding

Writing this review was supported by a NIH grant to Dr. Akhil B. Vaidya (AI028398) at the Center for Parasitology at Drexel University College of Medicine.

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  1. Center for Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, 19129, USA

    Hangjun Ke & Michael W. Mather

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Correspondence to Hangjun Ke.

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Dr. Hangjun Ke and Dr. Michael W. Mather are supported by an NIH grant (AI028398) to Dr. Akhil B. Vaidya.

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Ke, H., Mather, M.W. +Targeting Mitochondrial Functions as Antimalarial Regime, What Is Next?. Curr Clin Micro Rpt 4, 175–191 (2017). https://doi.org/10.1007/s40588-017-0075-5

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