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PreprintCited by 15Malaria Research and ControlMitochondrial Function and PathologyEnzyme Structure and Function

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Biogenesis of cytochromes c and c 1 in the electron transport chain of malaria parasites

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García-Guerrero, Aldo E., Marvin, Rebecca G., Blackwell, Amanda Mixon, Sigala, Paul A.·2024·ACS Infectious Diseases
DOI 10.1101/2024.02.01.575742PMC PMC11991887

Preprint — published as 10.1021/acsinfecdis.4c00450 · Paper page

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Abstract

Plasmodium malaria parasites retain an essential mitochondrional electron transport chain (ETC) that is critical for growth within humans and mosquitoes and a key antimalarial drug target. ETC function requires cytochromes c and c 1 that are unusual among heme proteins due to their covalent binding to heme via conserved CXXCH sequence motifs. Heme attachment to these proteins in most eukaryotes requires the mitochondrial enzyme holocytochrome c synthase (HCCS) that binds heme and the apo cytochrome to facilitate biogenesis of the mature cytochrome c or c 1 . Although humans encode a single bifunctional HCCS that attaches heme to both proteins, Plasmodium parasites are like yeast and encode two separate HCCS homologs thought to be specific for heme attachment to cyt c (HCCS) or cyt c 1 (HCC 1 S). To test the function and specificity of P. falciparum HCCS and HCC 1 S, we used CRISPR/Cas9 to tag both genes for conditional expression. HCC 1 S knockdown selectively impaired cyt c 1 biogenesis and caused lethal ETC dysfunction that was not reversed by over-expression of HCCS. Knockdown of HCCS caused a more modest growth defect but strongly sensitized parasites to mitochondrial depolarization by proguanil, revealing key defects in ETC function. These results and prior heterologous studies in E. coli of cyt c hemylation by P. falciparum HCCS and HCC 1 S strongly suggest that both homologs are essential for mitochondrial ETC function and have distinct specificities for biogenesis of cyt c and c 1 , respectively, in parasites. This study lays a foundation to develop novel strategies to selectively block ETC function in malaria parasites.

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Metadata

Authors
García-Guerrero, A. E., Marvin, R. G., Blackwell, A. M., & Sigala, P. A.
Affiliations
University of Utah (US)
Corresponding author
Sigala, Paul A.
ORCID
Venue
ACS Infectious Diseases
Publisher
openRxiv
Published
2024-02-01
Volume
11
Issue
4
Pages
813-826
ISSN
2373-8227 (ISSN-L)
DOI
10.1101/2024.02.01.575742
PMC
PMC11991887
OpenAlex
W4403925248
Cited by
15
References
1
Citations by year
2026: 4 · 2025: 5 · 2024: 6
FWCI
6.21
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Infectious Diseases (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Burroughs Wellcome Fund (1011969)
  • Pew Charitable Trusts (32099)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R35GM133764)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
cytochrome c, cytochrome c1, heme attachment, Plasmodium falciparum, mitochondrial electron transport chain, CXXCH motif, proguanil, mitochondrial depolarization, antimalarial drug targets, CRISPR/Cas9 knockdown

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