Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites

  1. Seyi Falekun
  2. Jaime Sepulveda
  3. Yasaman Jami-Alahmadi
  4. Hahnbeom Park
  5. James A Wohlschlegel
  6. Paul A Sigala  Is a corresponding author
  1. University of Utah School of Medicine, United States
  2. University of California, Los Angeles, United States
  3. University of Washington, United States

Abstract

Most eukaryotic cells retain a mitochondrial fatty acid synthesis (FASII) pathway whose acyl carrier protein (mACP) and 4-phosphopantetheine (Ppant) prosthetic group provide a soluble scaffold for acyl chain synthesis and biochemically couple FASII activity to mitochondrial electron transport chain (ETC) assembly and Fe-S cluster biogenesis. In contrast, the mitochondrion of Plasmodium falciparum malaria parasites lacks FASII enzymes yet curiously retains a divergent mACP lacking a Ppant group. We report that ligand-dependent knockdown of mACP is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from death, suggesting a dominant dysfunction of the mitochondrial ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 complex required for Fe-S cluster biosynthesis, despite lacking the Ppant group required for this association in other eukaryotes, and knockdown of parasite mACP causes loss of Nfs1 and the Rieske Fe-S protein in ETC Complex III. This work reveals that Plasmodium parasites have evolved to decouple mitochondrial Fe-S cluster biogenesis from FASII activity, and this adaptation is a shared metabolic feature of other apicomplexan pathogens, including Toxoplasma and Babesia. This discovery unveils an evolutionary driving force to retain interaction of mitochondrial Fe-S cluster biogenesis with ACP independent of its eponymous function in FASII.

Data availability

All data reported or analyzed in this manuscript are available and included in the main and supplemental figures and in the source data files.

Article and author information

Author details

  1. Seyi Falekun

    University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jaime Sepulveda

    University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yasaman Jami-Alahmadi

    University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hahnbeom Park

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. James A Wohlschlegel

    University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Paul A Sigala

    University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    p.sigala@biochem.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3464-3042

Funding

National Institute of General Medical Sciences (R35GM133764)

  • Paul A Sigala

National Institute of General Medical Sciences (R01GM089778)

  • James A Wohlschlegel

National Institute of Diabetes and Digestive and Kidney Diseases (U54DK110858)

  • Paul A Sigala

Burroughs Wellcome Fund (1011969)

  • Paul A Sigala

Pew Charitable Trusts (32099)

  • Paul A Sigala

National Institute of General Medical Sciences (T32GM122740)

  • Jaime Sepulveda

National Institutes of Health (S10OD018210)

  • Paul A Sigala

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Malcolm J McConville, The University of Melbourne, Australia

Version history

  1. Preprint posted: April 13, 2021 (view preprint)
  2. Received: June 25, 2021
  3. Accepted: October 6, 2021
  4. Accepted Manuscript published: October 6, 2021 (version 1)
  5. Version of Record published: October 26, 2021 (version 2)

Copyright

© 2021, Falekun et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Seyi Falekun
  2. Jaime Sepulveda
  3. Yasaman Jami-Alahmadi
  4. Hahnbeom Park
  5. James A Wohlschlegel
  6. Paul A Sigala
(2021)
Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
eLife 10:e71636.
https://doi.org/10.7554/eLife.71636

Share this article

https://doi.org/10.7554/eLife.71636

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