Mitochondria protect against an intracellular pathogen by restricting access to folate
As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen <i>Toxoplasma gondii</i>, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited <i>Toxoplasma</i> access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against <i>Toxoplasma</i>.
Authors
- Lilach Sheiner (ORCID: https://orcid.org/0000-0001-5909-2307)
- Lena Pernas (ORCID: https://orcid.org/0000-0002-4337-3435)
- Patrick Giavalisco (ORCID: https://orcid.org/0000-0002-4636-1827)
- Xianhe Li (ORCID: https://orcid.org/0000-0003-1099-518X)
- Jana Ovciarikova (ORCID: https://orcid.org/0000-0001-7522-8876)
- Tim Bartsch (ORCID: https://orcid.org/0000-0002-4041-1686)
- Bruna Martins Garcia (ORCID: https://orcid.org/0000-0002-2257-9370)
- Tania Medeiros (ORCID: https://orcid.org/0000-0001-5843-3763)
- Andrea Mesaros (ORCID: https://orcid.org/0000-0003-2394-1412)
- Nicholas D. E. Greene (ORCID: https://orcid.org/0000-0002-4170-5248)
- John Crow (ORCID: https://orcid.org/0000-0001-5155-5362)
- Martin Purrio
- Matías D. Hartman (ORCID: https://orcid.org/0000-0002-0839-2075)
- Kit‐Yi Leung (ORCID: https://orcid.org/0000-0002-7868-9616)
- Martin S. Denzel (ORCID: https://orcid.org/0000-0002-5691-3349)
- Kira Allmeroth (ORCID: https://orcid.org/0000-0002-2659-6776)
- Michelle Téllez-Sütterlin (ORCID: https://orcid.org/0009-0005-9708-6588)
- Irina Rais (ORCID: https://orcid.org/0000-0002-0367-1980)
- Silvia Reato
- Patrick Krueger
Institutions
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Wellcome Centre for Molecular Parasitology (GB)
- Max Planck Institute for Biology of Ageing (DE)
- University College London (GB)
Publication Details
- Journal
- Science
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1126/science.adr6326
- Citations
- 9
- Primary Topic
- Toxoplasma gondii Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 18.43