Amazing stuff! Did you take your vitamin supplement today?
"Key takeaways
- ... research shows that mitochondria detect invading pathogen Toxoplasma gondii and ramp up competition for vitamin B9, also known as folate, depriving it of the nourishment it needs to grow.
- This new discovery came about when a researcher noticed that the amount of mitochondrial DNA in a mitochondrion increased during an infection.
- The new discovery raises the possibility that a vitamin regimen could rewire mitochondrial metabolism to make it even more effective at preventing infections, such as toxoplasmosis, in people.
...
mitochondria starve pathogens by competing with them for vitamin B9 (folate) to prevent infection. The researchers found that the folate used by mitochondria as part of their normal metabolism reduced the amount of folate available to a specific parasite, Toxoplasma gondii, which subsequently grew more slowly. ..."
From the editor's summary and abstract:
"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. ...
Structured Abstract
INTRODUCTION
Mitochondria ... also use and consume many nutrients that invading pathogens rely on. ...
RATIONALE
... 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.
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