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Mitochondria protect against an intracellular pathogen by restricting access to folate

Tânia Catarina Medeiros1, Jana Ovciarikova2, Xianhe Li1

  • 1Metabolism of Infection Group, Max Planck Institute for Biology of Ageing, Cologne, Germany.

Science (New York, N.Y.)
|August 14, 2025
PubMed

Insights

The activating transcription factor 4 (ATF4) enhances mitochondrial folate metabolism to limit pathogen growth. This metabolic defense restricts Toxoplasma gondii by controlling essential nutrient access.

Area of Science:

  • Cellular metabolism
  • Mitochondrial biology
  • Infectious disease

Background:

  • Mitochondria are central to cellular metabolism and nutrient competition with pathogens.
  • The role of mitochondrial metabolism in host defense against infection is not fully understood.

Purpose of the Study:

  • To investigate if and how cells utilize mitochondrial metabolism for protection against microbial invasion.
  • To elucidate the role of activating transcription factor 4 (ATF4) in host defense.

Main Methods:

  • Infection of cultured mammalian cells with *Toxoplasma gondii*.
  • Analysis of mitochondrial DNA levels and one-carbon metabolism.
  • Investigating the role of ATF4 in regulating metabolic pathways.

Main Results:

  • ATF4 activation leads to increased mitochondrial DNA by promoting folate-dependent one-carbon metabolism.
  • Host detection of mitochondrial stress triggers ATF4.
  • ATF4 limits *Toxoplasma* access to folate, inhibiting parasite growth by restricting deoxythymidine monophosphate synthesis.

Conclusions:

  • ATF4 orchestrates a mitochondrial metabolic defense strategy against *Toxoplasma gondii*.
  • This defense relies on rewiring mitochondrial metabolism to control folate availability.
  • Mitochondrial metabolism plays a critical role in host-pathogen interactions.

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