2025-08-14 マックス・プランク研究所
<関連情報>
- https://www.mpg.de/25204418/mitochondria-defend-cells-against-infections
- https://www.science.org/doi/10.1126/science.adr6326
ミトコンドリアは葉酸へのアクセスを制限することで細胞内病原体から保護する Mitochondria protect against an intracellular pathogen by restricting access to folate
Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, […] , and Lena Pernas
Science Published:14 Aug 2025
DOI:https://doi.org/10.1126/science.adr6326
Editor’s summary
Mitochondria consume nutrients that are also needed by invading pathogens. Whether cells exploit this overlap for host defense has been unclear. Medeiros et al. found that cells harness mitochondrial metabolism to restrict access of the intracellular parasite Toxoplasma gondii to the essential B vitamin folate (see the Perspective by Suomalainen and Nikkanen). When host cells detect intracellular parasite effectors, they activate the integrated stress response and its key effector, ATF4. ATF4 induces one-carbon metabolism processes in host mitochondria that use folate. Because Toxoplasma requires folate to generate thymidine for DNA synthesis, ATF4 activation restricts parasite replication. Thus, infected cells can weaponize mitochondrial metabolism to defend against pathogens. —Stella M. Hurtley
Structured Abstract
INTRODUCTION
Mitochondria are key hubs of cellular metabolism. This means that in addition to generating a range of metabolites, these organelles also use and consume many nutrients that invading pathogens rely on. Although mitochondria number in the hundreds to up to the thousands in mammalian cells—in contrast to few invading pathogens—it remains unclear whether host cells leverage mitochondria to restrict pathogen access to essential metabolites.
RATIONALE
We reasoned that mitochondrial processes that rely on diverse cytosolic metabolites might reveal competing metabolic demands between mitochondria and intracellular pathogens. We focused on the replication of mitochondrial DNA (mtDNA), which requires nutrients including those that maintain one-carbon metabolism processes required for nucleotide biosynthesis. We found that infection with the intracellular parasite Toxoplasma gondii increased mtDNA copy number. This response was independent of mitochondrial biogenesis but required activating transcription factor 4 (ATF4), which was activated through the integrated stress response (ISR) kinase HRI in response to parasite effector–induced mitochondrial stress.
RESULTS
Having identified that Toxoplasma infection led to an increase in mtDNA in an ATF4-dependent manner, we next investigated the underlying mechanism. During infection, ATF4 induced the mitochondrial one-carbon enzymes MTHFD2 and SHMT2, which use folate to provide carbon units for biosynthetic pathways, such as nucleotide synthesis. Both ATF4 and MTHFD2 were required for the increase in mtDNA and for restricting parasite growth. We pinpointed this restriction to competition for folate, an essential cofactor that Toxoplasma requires to produce deoxythymidine monophosphate (dTMP) and to proliferate. Disrupting mitochondrial one-carbon metabolism—through ATF4 loss or methotrexate treatment—led to increased parasite dTMP synthesis and replication. In vivo, preventing ATF4 activation through pharmacological inhibition of the ISR similarly elevated parasite burden.
CONCLUSION
We discovered a host defense strategy rooted in metabolic competition between mitochondria and an intracellular pathogen. This defense was mediated by the ISR effector ATF4, which was activated in response to the detection of parasite effector–induced mitochondrial stress. ATF4 enhanced mitochondrial one-carbon metabolism, thereby depriving Toxoplasma gondii of host folate(s) and limiting its ability to synthesize dTMP and proliferate. Thus, mitochondria execute a noncanonical metabolic defense against an intracellular pathogen. We propose that these organelles are positioned to compete with other intracellular pathogens for nutrients, such as folate, that are essential for their replication.
Host cells weaponize mitochondrial metabolism.
Upon detection of secreted parasite effectors, host cells activate the ISR. The ISR effector ATF4 increases mtDNA levels and induces mitochondrial one-carbon (mito-1C) metabolism, thereby restricting Toxoplasma access to the folate(s) that it requires for dTMP synthesis and growth.
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.
