Malaria remains a major global health burden and affects 40% of the world’s population. Each year, this disease alone causes over 200 million illnesses and kills more than half a million lives. In recent years, malaria control has been impeded by drug resistance to almost all available antimalarials. Identifying new drug targets and understanding their modes of action are critical for developing new treatments.

Dr. Ke’s laboratory studies malaria parasites, in particularly Plasmodium falciparum, the most lethal form among five species that cause human malaria. Using P. falciparum as a model, the overall goal is to characterize essential pathways of the parasite for developing novel antimalarial drugs.

Lab Members

• Graduate student: Ikechukwu Nwankwo
• Former members: Dr. Swati Dass (2022), Dr. Maruthi Mulaka (2020), Dr. Liqin Ling (2019), Neeta Shadija (MS, 2022), Omobukola Solebo (MS, 2021)

The intraerythrocytic developmental cycle of Plasmodium falciparum, from L-R: merozoite, ring, trophozoite and schizont

pH Regulation and Proton Pumps

Proton pumps are central to the development of malaria parasites over the complex life cycle. They pump protons cross membranes to 1) establish a plasma membrane potential, 2) remove extra acids from the cytosol, and 3) acidify intracellular organelles such as the digestive vacuole. The parasite plasma membrane potential is vital for importing nutrients and exporting waste products. The cytosolic pH is maintained in a narrow range to ensure all biological reactions are conducted in the appropriate pH environment. The parasite’s digestive vacuole requires a low pH to digest a large volume of host derived hemoglobin. Malaria parasites encode several types of proton pumps, including vacuolar pyrophosphates and V-type ATPase. The Ke’s lab has identified the vacuolar pyrophosphatase 1, PfVP1, is essential for parasite development in the ring stage and the transition to the trophozoite stage. Located on the parasite plasma membrane, PfVP1 is an ATP independent proton pump that utilizes pyrophosphate as energy. The lab is also investigating the localization and function of the parasite V-type ATPase, an ATP dependent proton pump made of ~ 30 proteins.

Bioenergetics of Malaria Parasites

Pyrophosphate (PPi) stores a significant amount of energy in its phosphoanhydride bond. It is an ancient energy source but is also a by-product of many synthetic reactions such as DNA, RNA, and protein synthesis. Humans have lost the ability to utilize PPi as energy because they don’t encode any membrane-bound pyrophosphatases. By contrast, malaria parasites encode two membrane-bound pyrophosphatases, PfVP1 and PfVP2. They pump protons across the membranes by re-utilizing the energy released from PPi hydrolysis. The Ke’s lab has discovered that PPi is a critical energy source for the malaria parasite to survive in the ring stage and the transition to the trophozoite stage. The lab is investigating where PPi is derived from and how it is degraded by membrane-bound and soluble pyrophosphatases.

Mitochondrial Dynamics, Morphology and Function

Mitochondria trace their origin from the symbiotic union of an alpha-proteobacterium and an ancient proto-eukaryote. From this single symbiotic event, and over millions of years under various evolutionary forces, the mitochondrion has evolved a tremendous diversity of its structure and function among the multitude of extant eukaryotes. This diversity allows eukaryotic organisms to occupy wide-ranging and diverse environmental niches on the planet. Nearly all eukaryotes have mitochondria or mitochondrially derived organelles, relying on mitochondria for energy, metabolites, essential cofactors, and/or signaling, including regulation of cellular life and death events. The phylum Apicomplexa comprises a vast group of single-celled protists, including ~ 5000 named species and over a million unnamed species. All apicomplexans are parasitic, including medically important parasites that can cause diseases like malaria, Toxoplasmosis, Cryptosporidiosis, Babesiosis, and Isosporiasis. The mitochondria of pathogenic protists are very divergent from the counterparts of humans, which could provide a foundation for selective toxicity that facilitates drug development.

View the complete list of publication from NCBI at https://www.ncbi.nlm.nih.gov/myncbi/hangjun.ke.1/bibliography/public/

Selected Publications

(*, corresponding author)

"Transcriptional changes in Plasmodium falciparum upon conditional knock down of mitochondrial ribosomal proteins RSM22 and L23"
Dass S, Mather M, Morrisey JM, Vaidya AB, Ke H*
PLoS One. 2022 Oct 6;17(10):e0274993. doi: 10.1371/journal.pone.0274993

"Design, synthesis, and biological evaluation of multiple targeting antimalarials"
Yang Y, Tang T, Li X, Michel T, Ling L, Huang Z, Mulaka M, Wu Y, Gao H, Wang L, Zhou J, Meunier B, Ke H, Jiang L, Rao Y
Acta Pharm Sin B. 2021 Sep;11(9):2900-2913. doi: 10.1016/j.apsb.2021.05.008

"A dispensable role of mitochondrial fission protein 1 (Fis1) in the erythrocytic development of Plasmodium falciparum"
Mulaka M, Ling L, Zhou J, Ke H*
mSphere. 2020 Sep 23;5(5):e00579-20. doi: 10.1128/mSphere.00579-20

"Genetic ablation of the mitoribosome in the malaria parasite Plasmodium falciparum sensitizes it to antimalarials that target mitochondrial function"
Ling L, Mulaka M, Munro J, Dass S, Mather MW, Riscoe MK, Llinás M, Zhou J, Ke H*
J Biol Chem. 2020 Apr 9. pii: jbc.RA120.012646. doi: 10.1074/jbc.RA120.012646

"Divergent Mitochondrial Ribosomes in Unicellular Parasitic Protozoans"
Dass S, Mather MW, Ke H*
Trends Parasitol. 2020 Apr;36(4):318-321. doi: 10.1016/j.pt.2020.01.002. Epub 2020 Feb 19

"Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages"
*Ke H, Ganesan SM, Dass S, Morrisey JM, Pou S, Nilsen A, Riscoe MK, Mather MW, Vaidya AB
PLoS One. 2019 Apr 9;14(4):e0214023. PMID: 30964863

"The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum"
*Ke H, Dass S, Morrisey JM, Mather MW, Vaidya AB
J Biol Chem. 2018 May 25;293(21):8128-8137. PMID: 29626096.

"Targeting mitochondrial functions as antimalarial regime, what is next? Current Clinical Microbiology Reports"
*Ke H, Mather MW
Curr Clin Micro Rpt 4:175–191, March 2017

"Caged Garcinia Xanthones, a novel chemical scaffold with potent antimalarial activity"
*Ke H, Morrisey JM, Qu S, Chantarasriwong O, Mather MW, Theodorakis EA, Vaidya AB
Antimicrob Agents Chemother.; 61(1), Dec 27, 2016

"Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle"
Ke H, Lewis IA, Morrisey JM, McLean KJ, Ganesan SM, Painter HJ, Mather MW, Jacobs-Lorena M, Llinás M, Vaidya AB
Cell Rep.;11(1):164-74, Apr 7, 2015

"The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages"
Ke H, Sigala PA, Miura K, Morrisey JM, Mather MW, Crowley JR, Henderson JP, Goldberg DE, Long CA, Vaidya AB
J Biol Chem. Dec 12; 289(50):34827-37, 2014

"The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain"
Ehrhardt K, Davioud-Charvet E, Ke H, Vaidya AB, Lanzer M, Deponte M
Antimicrob Agents Chemother.; 57(5):2114-20, May 2013

"Mitochondrial RNA polymerase is an essential enzyme in erythrocytic stages of Plasmodium falciparum"
Ke H, Morrisey JM, Ganesan SM, Mather MW, Vaidya AB
Mol Biochem Parasitol.; 185(1):48-51, Sep 2012

"ATP synthase complex of Plasmodium falciparum: dimeric assembly in mitochondrial membranes and resistance to genetic disruption"
Balabaskaran Nina P, Morrisey JM, Ganesan SM, Ke H, Pershing AM, Mather MW, Vaidya AB
J Biol Chem.; 286(48):41312-22, Dec 2, 2011

"A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor"
McCormack S, Bursulaya B, Ke H, Vaidya AB, Schultz PG, Winzeler EA
ACS Chem Biol.; 6(11):1214-22, Nov 18, 2011

"Variation among Plasmodium falciparum strains in their reliance on mitochondrial electron transport chain function"
Ke H, Morrisey JM, Ganesan SM, Painter HJ, Mather MW, Vaidya AB
Eukaryot Cell.; 10(8):1053-61, Aug 2011

"Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection"
Ganesan SM, Morrisey JM, Ke H, Painter HJ, Laroiya K, Phillips MA, Rathod PK, Mather MW, Vaidya AB
Mol Biochem Parasitol.; 177(1):29-34, May 2011