Mitochondria Deprive Parasites of Folate to Thwart Their Growth
Parasitic infection in cultured cells prompted mitochondria to consume more folate, leaving less of the essential nutrient for the microbe to grow.
Source: www.the-scientist.com, by Andrew Saintsing, Aug 28, 2025
Folate, or vitamin B9, is an essential nutrient. Without it, individual cells could not replicate their DNA or make copies of themselves, and consequently, the body would not be able to grow or replace old, damaged tissue. So, doctors recommend that women who are planning to become pregnant take prenatal vitamins loaded with folic acid, the synthetic version of folate.1
Mitochondria produce energy, but they may also help cells fight intracellular pathogens by hoarding essential nutrients to starve the invaders. Image credit:© iStock, wir0man
As it turns out, this pharmaceutical strategy of starving fast-dividing cells of folate may have a natural precedent. According to new research led by Lena Pernas, a microbiologist at the University of California, Los Angeles, proteins released by an intracellular parasite can trigger mitochondria to deplete the cell’s folate by using it themselves.4 The findings, published in Science, could open up new treatment strategies for starving pathogenic microbes of the nutrients they need to sustain infections.
“If we can find more targeted ways to limit those nutrients—for example, by boosting mitochondrial health or boosting the ability of mitochondria to take them—then it’s one way to increase the ability of an organism to defend against that pathogen,” said Pernas.
Pernas has been studying interactions between mitochondria and parasites since she was a graduate student. Early on, her PhD adviser showed her a microscopic image of the energy-producing organelles surrounding a Toxoplasma gondii parasite—the eukaryotic microbe that makes rodents more likely to get themselves eaten and causes toxoplasmosis in some of the many humans it infects—in a mammalian cell.5,6
“Why are the mitochondria there?” she wondered.
The more she thought about it, the more Pernas began to see the mitochondria as participants in the cell’s defense response. Rather than directly attacking pathogenic invaders like a white blood cell would, Pernas realized that mitochondria were better equipped to fight intracellular parasites by competing with them for nutrients. The interior of a cell has finite resources, and if mitochondria start using more of something essential, like folate, then there is less of it available for parasites.
To put this theory to the test, Pernas’s team infected various types of cultured human cells with T. gondii parasites and tracked changes in the host cells’ mitochondria. The scientists observed that the amount of mitochondrial DNA in each cell increased, even though the number of mitochondria did not change. This suggested that mitochondria were not simply multiplying but rather ramping up DNA synthesis.
Pernas and her team investigated what signals could lead to this response by looking for infection-driven changes in the quantities of various proteins. They observed high levels of activating transcription factor 4 (ATF4), which helps carry out the integrated stress response in eukaryotic cells facing lack of nutrients or infections.
To confirm that the infectious parasite, rather than its consumption of nutrients, triggered the integrated stress response, the scientists infected cells with a mutant version of T. gondii. The modified T. gondii, which were incapable of releasing a cocktail of proteins to alter the conditions within its host cell, did not trigger the integrated stress response.
Finally, the researchers found that an increase in ATF4 levels led to increased numbers of folate-metabolizing enzymes, ultimately enhancing mitochondrial DNA synthesis, which was reversed on blocking the integrated stress response. In those cases, there was more folate available, and the T. gondii parasites grew faster both in vitro in human cells and in vivo in mice.
Giel van Dooren, a microbiologist at the Australian National University who was not involved in the study, was fascinated by Pernas’s work. But he wondered how she could be entirely sure that the process she had uncovered was beneficial for host cells and detrimental for the parasites. “The host cell is responding to something that the parasite is secreting into it,” he said. “Perhaps the parasite is somehow modulating the host cell on purpose.” For instance, the T. gondii parasite, which causes no apparent symptoms in most of the people it infects, may benefit from limiting its own growth to ensure the continued viability of its host.
In the future, van Dooren hopes that Pernas will study other parasites to see if this is a universal cellular response to invasion. Pernas’s lab has already begun a project focused on chlamydia-causing bacteria since those microbes have a similar tendency to associate with their host’s mitochondria. But she hopes her findings will also be helpful to scientists studying malaria, which is caused by eukaryotic Plasmodium parasites, which are related to T. gondii.
Plasmodium parasites are so reliant on folate for rapid growth that public health officials hesitate to recommend folic acid supplements in regions with a high prevalence of malaria.7 Because the nutrient is so important to these organisms, resistance to drugs that target folate metabolism can spread rapidly, leaving people with fewer treatment options.8
While more work is needed before these results can guide the development of new therapeutic strategies, at the very least, Pernas hopes that the study reinforces the fact that “it’s really important to consider nutrients and vitamins during infection.”
