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@ARTICLE{Wunderlich:635879,
      author       = {Wunderlich, Juliane and Kotov, Vadim and Votborg-Novél,
                      Lasse and Ntalla, Christina and Geffken, Maria and Peine,
                      Sven and Portugal, Silvia and Strauss, Jan},
      title        = {{I}ron transport pathways in the human malaria parasite
                      {P}lasmodium falciparum revealed by {RNA}-sequencing},
      journal      = {Frontiers in Cellular and Infection Microbiology},
      volume       = {14},
      issn         = {2235-2988},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {PUBDB-2025-03563},
      pages        = {1480076},
      year         = {2024},
      abstract     = {Host iron deficiency is protective against severe malaria
                      as the human malaria parasite Plasmodium falciparum depends
                      on bioavailable iron from its host to proliferate. The
                      essential pathways of iron acquisition, storage, export, and
                      detoxification in the parasite differ from those in humans,
                      as orthologs of the mammalian transferrin receptor,
                      ferritin, or ferroportin, and a functional heme oxygenase
                      are absent in P. falciparum. Thus, the proteins involved in
                      these processes may be excellent targets for therapeutic
                      development, yet remain largely unknown. Here, we show that
                      parasites cultured in erythrocytes from an iron-deficient
                      donor displayed significantly reduced growth rates compared
                      to those grown in red blood cells from healthy controls.
                      Sequencing of parasite RNA revealed diminished expression of
                      genes involved in overall metabolism, hemoglobin digestion,
                      and metabolite transport under low-iron versus control
                      conditions. Supplementation with hepcidin, a specific
                      ferroportin inhibitor, resulted in increased labile iron
                      levels in erythrocytes, enhanced parasite replication, and
                      transcriptional upregulation of genes responsible for
                      merozoite motility and host cell invasion. Through
                      endogenous GFP tagging of differentially expressed putative
                      transporter genes followed by confocal live-cell imaging,
                      proliferation assays with knockout and knockdown lines, and
                      protein structure predictions, we identified six proteins
                      that are likely required for ferrous iron transport in P.
                      falciparum. Of these, we localized PfVIT and PfZIPCO to
                      cytoplasmic vesicles, PfMRS3 to the mitochondrion, and the
                      novel putative iron transporter PfE140 to the plasma
                      membrane for the first time in P. falciparum. PfNRAMP/PfDMT1
                      and PfCRT were previously reported to efflux Fe$^{2+}$ from
                      the digestive vacuole. Our data support a new model for
                      parasite iron homeostasis, in which PfE140 is involved in
                      iron uptake across the plasma membrane, PfMRS3 ensures
                      non-redundant Fe$^{2+}$ supply to the mitochondrion as the
                      main site of iron utilization, PfVIT transports excess iron
                      into cytoplasmic vesicles, and PfZIPCO exports Fe$^{2+}$
                      from these organelles in case of iron scarcity. These
                      results provide new insights into the parasite’s response
                      to differential iron availability in its environment and
                      into the mechanisms of iron transport in P. falciparum as
                      promising candidate targets for future antimalarial drugs.},
      cin          = {CSSB-EMBL-CL},
      ddc          = {610},
      cid          = {I:(DE-H253)CSSB-EMBL-CL-20210806},
      pnm          = {899 - ohne Topic (POF4-899) / DrySeasonPf - Dry season P.
                      falciparum reservoir (759534)},
      pid          = {G:(DE-HGF)POF4-899 / G:(EU-Grant)759534},
      experiment   = {EXP:(DE-H253)ALFM-20250101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39575308},
      doi          = {10.3389/fcimb.2024.1480076},
      url          = {https://bib-pubdb1.desy.de/record/635879},
}