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The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.

ABSTRACT: To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen Plasmodium falciparum employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.

SUBMITTER: Alder A

PROVIDER: S-EPMC10372686 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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The role of <i>Plasmodium</i> V-ATPase in vacuolar physiology and antimalarial drug uptake.

Alder Arne A Sanchez Cecilia P CP Russell Matthew R G MRG Collinson Lucy M LM Lanzer Michael M Blackman Michael J MJ Gilberger Tim-Wolf TW Matz Joachim M JM

Proceedings of the National Academy of Sciences of the United States of America 20230718 30

To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen <i>Plasmodium falciparum</i> employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. ...[more]

PMID: 37463201

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Project description:Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F1-γ-subunit of the two-sector F1Fo-ATP synthase allow for Fo-independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal Fo-A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.

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The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.

Publications

The role of <i>Plasmodium</i> V-ATPase in vacuolar physiology and antimalarial drug uptake.

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Dataset Information

The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.

Publications

The role of &lt;i&gt;Plasmodium&lt;/i&gt; V-ATPase in vacuolar physiology and antimalarial drug uptake.

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OmicsDI is part of the ELIXIR infrastructure

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The role of <i>Plasmodium</i> V-ATPase in vacuolar physiology and antimalarial drug uptake.