Medeiros, Tânia Catarina;
Ovciarikova, Jana;
Li, Xianhe;
Krueger, Patrick;
Bartsch, Tim;
Reato, Silvia;
Crow, John C;
... Pernas, Lena; + view all
(2025)
Mitochondria protect against an intracellular pathogen by restricting access to folate.
Science
, 389
(6761)
, Article eadr6326. 10.1126/science.adr6326.
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Abstract
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 Toxoplasma gondii, 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 Toxoplasma 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 Toxoplasma.
| Type: | Article |
|---|---|
| Title: | Mitochondria protect against an intracellular pathogen by restricting access to folate |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/science.adr6326 |
| Publisher version: | https://doi.org/10.1126/science.adr6326 |
| Language: | English |
| Additional information: | Copyright © 2025 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science- licenses- journal- article-reuse. This article is subject to HHMI’s Open Access to Publications policy. HHMI lab headshave previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. This research was also funded in whole or in part by the Medical Research Council (W00500X) and Wellcome (217173_Z_19_Z), cOAlition Sorganizations, and by the European Research Council (ERC-StG- 2019 852457); as required, the author will make the Author Accepted Manuscript (AAM) version available under a CC BY public copyright license. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, TOXOPLASMA-GONDII, REPLICATION, METABOLISM, EXPRESSION, DEFECTS, GROWTH |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213167 |
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