The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum

The phylum Apicomplexa contains a group of protozoa causing diseases in humans and livestock. Plasmodium spp., the causative agent of malaria, contains a mitochondrion that is very divergent from that of their hosts. The malarial mitochondrion is a clinically validated target for the antimalarial dr...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-05, Vol.293 (21), p.8128-8137
Main Authors: Ke, Hangjun, Dass, Swati, Morrisey, Joanne M., Mather, Michael W., Vaidya, Akhil B.
Format: Article
Language:English
Subjects:
Antimalarials - pharmacology
apicomplexan
Cell Biology
Electron Transport
Genome, Mitochondrial
Humans
malaria
Malaria - drug therapy
Malaria - metabolism
Malaria - parasitology
Membrane Potential, Mitochondrial
mitochondria
Mitochondria - chemistry
Mitochondria - drug effects
Mitochondria - metabolism
mitochondrial DNA (mtDNA)
mitochondrial genome
mitochondrial ribosome
mitochondrion
mitoribosome
mRPL13
Oxidoreductases Acting on CH-CH Group Donors - genetics
Oxidoreductases Acting on CH-CH Group Donors - metabolism
parasitology
plasmodium
Plasmodium falciparum - drug effects
Plasmodium falciparum - isolation & purification
Plasmodium falciparum - metabolism
ribosomal protein
Ribosomal Proteins - genetics
Ribosomal Proteins - metabolism
ribosome
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Summary:The phylum Apicomplexa contains a group of protozoa causing diseases in humans and livestock. Plasmodium spp., the causative agent of malaria, contains a mitochondrion that is very divergent from that of their hosts. The malarial mitochondrion is a clinically validated target for the antimalarial drug atovaquone, which specifically blocks the electron transfer activity of the bc1 complex of the mitochondrial electron transport chain (mtETC). Most mtETC proteins are nuclear-encoded and imported from the cytosol, but three key protein subunits are encoded in the Plasmodium mitochondrial genome: cyt b, COXI, and COXIII. They are translated inside the mitochondrion by mitochondrial ribosomes (mitoribosomes). Here, we characterize the function of one large mitoribosomal protein in Plasmodium falciparum, PfmRPL13. We found that PfmRPL13 localizes to the parasite mitochondrion and is refractory to genetic knockout. Ablation of PfmRPL13 using a conditional knockdown system (TetR-DOZI-aptamer) caused a series of adverse events in the parasite, including mtETC deficiency, loss of mitochondrial membrane potential (Δψm), and death. The PfmRPL13 knockdown parasite also became hypersensitive to proguanil, a drug proposed to target an alternative process for maintaining Δψm. Surprisingly, transmission EM revealed that PfmRPL13 disruption also resulted in an unusually elongated and branched mitochondrion. The growth arrest of the knockdown parasite could be rescued with a second copy of PfmRPL13, but not by supplementation with decylubiquinone or addition of a yeast dihydroorotate dehydrogenase gene. In summary, we provide first and direct evidence that mitoribosomes are essential for malaria parasites to maintain the structural and functional integrity of the mitochondrion.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.002552