Mitochondria protect against an intracellular pathogen by restricting access to folate

• 成果类型: Article
• 署名作者: Medeiros, Tania Catarina; Ovciarikova, Jana; Li, Xianhe; Krueger, Patrick; Bartsch, Tim; Reato, Silvia; Crow, John C.; Tellez Sutterlin, Michelle; Martins Garcia, Bruna; Rais, Irina; Allmeroth, Kira; Hartman, Matias D.; Denzel, Martin S.; Purrio, Martin; Mesaros, Andrea; Leung, Kit-Yi; Greene, Nicholas D. E.; Sheiner, Lilach; Giavalisco, Patrick; Pernas, Lena
• 署名单位: Max Planck Society; University of Glasgow; University of California System; University of California Los Angeles; Howard Hughes Medical Institute; University of California System; University of California Los Angeles; Max Planck Society; Max Planck Society; University of London; University College London; Max Planck Society
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11338
• DOI: 10.1126/science.adr6326
• 发表日期: 2025-08-14
• 关键词: toxoplasma-gondii; replication; metabolism; expression; defects; GROWTH

摘要

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.