Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis DOI Open Access
Amanda Mixon Blackwell, Yasaman Jami‐Alahmadi, Armiyaw S. Nasamu

et al.

Published: Aug. 27, 2024

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO activity. The cellular role this underpins its retention by been unknown. To unravel PfHO function, we first determined 2.8 Å-resolution X-ray structure revealed highly α-helical fold indicative distant homology. Localization studies unveiled targeting to apicoplast organelle, where it imported undergoes N-terminal processing but retains electropositive transit peptide. We observed conditional knockdown was lethal parasites, died from defective biogenesis impaired isoprenoid-precursor synthesis. Complementation molecular-interaction an essential N-terminus PfHO, selectively associates with genome enzymes involved in nucleic acid metabolism gene expression. resulted specific deficiency levels apicoplast-encoded RNA not DNA. These reveal function maintenance suggest repurposed conserved scaffold heme-degrading ancestral chloroplast fulfill critical adaptive organelle

Language: Английский

Biogenesis of cytochromescandc1in the electron transport chain of malaria parasites DOI Creative Commons
Aldo E. García-Guerrero,

Rebecca G. Marvin,

Amanda Mixon Blackwell

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

malaria parasites retain an essential mitochondrional electron transport chain (ETC) that is critical for growth within humans and mosquitoes a key antimalarial drug target. ETC function requires cytochromes

Language: Английский

Citations

9
Plasmodium falciparum Mitochondrial Complex III, the Target of Atovaquone, Is Essential for Progression to the Transmissible Sexual Stages DOI Open Access
Pradeep Kumar Sheokand,

Sabyasachi Pradhan,

Andrew E. Maclean

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9239 - 9239

Published: Aug. 26, 2024

The

Language: Английский

Citations

5
Biogenesis of Cytochromes c and c1 in the Electron Transport Chain of Malaria Parasites DOI
Aldo E. García-Guerrero,

Rebecca G. Marvin,

Amanda Mixon Blackwell

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

malaria parasites retain an essential mitochondrional electron transport chain (ETC) that is critical for growth within humans and mosquitoes a key antimalarial drug target. ETC function requires cytochromes

Language: Английский

Citations

5
Mechanisms of Mitochondria-Mediated Apoptosis During Eimeria tenella Infection DOI Creative Commons
Rui Bai, Hui Wang,

Tiantian Yang

et al.

Animals, Journal Year: 2025, Volume and Issue: 15(4), P. 577 - 577

Published: Feb. 17, 2025

Coccidiosis in chickens is a parasitic disease caused by Eimeria species, resulting significant economic losses to the poultry industry. Among these tenella considered most virulent pathogen, with its infection strongly associated apoptotic response of host cells. modulates cell apoptosis stage-specific manner, suppressing early phase promote intracellular development and triggering later stages facilitate parasite egress progression. This study established an vitro model using 60 fifteen-day-old chick embryo cecal epithelial cells infecting sporozoites at 1:1 ratio sporozoites. The aim was examine relationship between infected E. tenella. roles mitochondrial permeability transition pore (MPTP) cytochrome c intrinsic were examined through application cyclosporine A (CsA), N, N', N'-tetramethyl-1,4-phenylenediamine (TMPD), ascorbate (Asc). TUNEL staining, ELISA, flow cytometry performed evaluate rates. CsA, TMPD, Asc significantly (p < 0.01) decreased release, caspase-9 activation, rates from 24 120 h post-E. infection. These findings highlight significance c-mediated, mitochondria-dependent pathways parasitized

Language: Английский

Citations

0
A tale of two parasites: a glimpse into the RNA methylome of patient-derived Plasmodium falciparum and Plasmodium vivax isolates DOI Creative Commons
Priyanka Roy,

Sukriti Gujarati,

Pallavi Gupta

et al.

Malaria Journal, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 2, 2025

Abstract Background Understanding the molecular mechanisms of malarial parasites in hosts is crucial for developing effective treatments. Epitranscriptomic research on pathogens has unveiled significance RNA methylation gene regulation and pathogenesis. This first report investigating signatures alternative splicing events using Nanopore Direct Sequencing to single-base resolution Plasmodium falciparum vivax clinical isolates with hepatic dysfunction complications. Methods from P. showing manifestation was performed. Subsequently, transcriptome reconstruction FLAIR transcript classification SQANTI3, followed by detection CHEUI m6Anet identify N6-methyladenosine (m6A) 5-methylcytosine (m5C) signatures, done. The both datasets were documented. Results reference genome reports > 5000 genes out which ~ 50% identified as expressed two sequenced isolates, including novel isoforms intergenic transcripts, highlighting extensive diversity. distinct profiles m6A m5C transcripts observed sense, Natural Antisense Transcripts (NATs) categories hinting at species-specific regulatory mechanisms. Dual modification a significant number parasites. Modified originating apicoplast mitochondrial genomes have also been detected. These modifications are unevenly present annotated regions mRNA, potentially influencing mRNA export translation. Several observed, 3′ 5′ end predominating suggesting differences translational kinetics possible protein characteristics these disease conditions. Conclusion data shows presence modified NATs alternatively spliced transcripts. phenomena together suggest multiple layers decides post-translational proteome particular Studies like will help decipher environments malaria vivo elucidate their inherent plasticity, thus allowing conceptualization strategies interventions.

Language: Английский

Citations

0
Plasmodium falciparummitochondrial complex III, the target of atovaquone, is essential for progression to the transmissible sexual stages DOI Open Access
Pradeep Kumar Sheokand, Alexander Mühleip, Lilach Sheiner

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 9, 2024

Abstract The Plasmodium mitochondrial electron transport chain (mETC) is responsible for essential metabolic pathways such as de novo pyrimidine synthesis and ATP synthesis. mETC complex III (cytochrome bc1 complex) transferring electrons from ubiquinol to cytochrome c generating a proton gradient across the inner membrane, which necessary function of synthase. Recent studies revealed that composition divergent human, highlighting its suitability target specific inhibition. Indeed, clinically used anti-malarial atovaquone several inhibitors undergoing pre-clinical trials, yet role in parasite biology have not been thoroughly studied. We provide evidence universally conserved subunit, PfRieske, new PfC3AP2, are part falciparum (PfCIII), with latter providing support prediction composition. Using inducible depletion, we show therefore PfCIII whole, asexual blood stage survival, line previous observations. further found depletion results gametocyte maturation defect. These phenotypes linked defects functions upon PfRieske including increased sensitivity stages decreased cristae abundance alongside abnormal morphology gametocytes. This first study explores direct gametogenesis via genetic disruption, paving way better understanding life cycle these important parasites focus antimalarial drug development on this pathway.

Language: Английский

Citations

3
Recombinant Biogenesis and Analysis of Cytochrome c Species DOI
Alicia N. Kreiman, Tania Yeasmin, Molly C. Sutherland

et al.

Methods in molecular biology, Journal Year: 2024, Volume and Issue: unknown, P. 195 - 211

Published: Jan. 1, 2024

Language: Английский

Citations

2
Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites DOI Creative Commons
Kade M. Loveridge, Paul A. Sigala

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(45)

Published: Oct. 28, 2024

Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. requires nutritional iron to support essential metabolic pathways, but critical mechanisms of acquisition trafficking during RBC infection have remained obscure. Parasites internalize liberate massive amounts heme large-scale digestion hemoglobin within an acidic food vacuole (FV) lack a oxygenase release porphyrin-bound iron. Although FV is sequestered into inert hemozoin crystals, prior studies indicate that trace escapes biomineralization susceptible nonenzymatic degradation oxidizing environment labile retain homolog divalent metal transporter 1 (DMT1), known mammalian transporter, its role has not been tested. Our phylogenetic DMT1 (PfDMT1) retains conserved molecular features for transport. We localized this protein membrane defined orientation export-competent topology. Conditional knockdown PfDMT1 expression lethal parasites, which display broad cellular defects iron-dependent functions, including impaired apicoplast biogenesis mitochondrial polarization. are selectively rescued from partial by supplementation with exogenous iron, other metals. These results paradigm whereby gatekeeper blood-stage suggest therapeutic targeting may be potent antimalarial strategy.

Language: Английский

Citations

2
Unraveling mechanisms of iron acquisition in malaria parasites DOI
Kade M. Loveridge, Paul A. Sigala

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

ABSTRACT Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. requires nutritional iron to support essential metabolic pathways, but critical mechanisms of acquisition trafficking during RBC infection have remained obscure. Parasites internalize liberate massive amounts heme large-scale digestion hemoglobin within an acidic food vacuole (FV) lack a oxygenase release porphyrin-bound iron. Although FV is sequestered into inert hemozoin crystals, prior studies indicate that trace escapes biomineralization susceptible non-enzymatic degradation oxidizing environment labile retain homolog divalent metal transporter 1 (DMT1), known mammalian transporter, its role has not been tested. Our phylogenetic DMT1 (PfDMT1) retains conserved molecular features for transport. We localized this protein membrane defined orientation export-competent topology. Conditional knockdown PfDMT1 expression lethal parasites, which display broad cellular defects iron-dependent functions, including impaired apicoplast biogenesis mitochondrial polarization. are selectively rescued from partial by supplementation with exogenous iron, other metals. These results paradigm whereby gatekeeper blood-stage suggest therapeutic targeting may be potent antimalarial strategy.

Language: Английский

Citations

1
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis DOI Creative Commons
Amanda Mixon Blackwell, Yasaman Jami‐Alahmadi, Armiyaw S. Nasamu

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Aug. 27, 2024

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO activity. The cellular role this underpins its retention by been unknown. To unravel PfHO function, we first determined 2.8 Å-resolution X-ray structure revealed highly α-helical fold indicative distant homology. Localization studies unveiled targeting to apicoplast organelle, where it imported undergoes N-terminal processing but retains electropositive transit peptide. We observed conditional knockdown was lethal parasites, died from defective biogenesis impaired isoprenoid-precursor synthesis. Complementation molecular-interaction an essential N-terminus PfHO, selectively associates with genome enzymes involved in nucleic acid metabolism gene expression. resulted specific deficiency levels apicoplast-encoded RNA not DNA. These reveal function maintenance suggest repurposed conserved scaffold heme-degrading ancestral chloroplast fulfill critical adaptive organelle

Language: Английский

Citations

1