UCLA researchers have identified a new way that cells fight off infection, revealing that mitochondria play an active role in defending against the parasite Toxoplasma gondii. The study, published in Science, found that mitochondria compete with this pathogen for vitamin B9 (folate), limiting the nutrient supply and slowing the parasite’s growth.
Toxoplasma gondii is transmitted through cat feces or undercooked meat and causes toxoplasmosis. While often symptomless, it can be dangerous for people with weakened immune systems and during pregnancy, potentially affecting fetal development.
The research team observed that during infection, mitochondrial DNA levels increased within cells. “A lot of people think of mitochondria as energy factories, and that pathogens can just exploit the powerhouse by consuming the energy they generate,” said Lena Pernas, corresponding author and UCLA professor of microbiology, immunology and molecular genetics. “But the reality is that mitochondria are actually a kind of domesticated bacteria that compete with invading pathogens for nutrients.”
Mitochondria originated from ancient bacteria through endosymbiosis—a process where one cell absorbed another to form a mutually beneficial relationship. These organelles still contain their own DNA.
“If we think about mitochondria as domesticated intracellular bacteria that want to protect their cell from new invaders, what’s a very simple way they could potentially do that?” Pernas explained. “Well, they could use up the nutrients that invaders rely on. And there are hundreds to thousands of mitochondria per cell and likely only a few initial invaders at any given time, which means there may not be a lot of nutrients left for the invaders.”
First author Tânia Catarina Medeiros noticed an increase in mitochondrial DNA during infection while working at the Max Planck Institute for Biology of Ageing. Experiments showed infected human cells produced more ATF4 protein—a regulator activated by stress such as microbial invasion—which led to higher mitochondrial metabolism.
“Pathogens have an arsenal of effectors, which are proteins that go into the host cell and perturb cell function. But the host cell was able to say to the mitochondria, ‘Hey, we’re detecting the proteins of this invader. Let’s activate this response,’” Pernas said.
When researchers deleted ATF4 from cells, parasites thrived—suggesting increased mitochondrial activity suppresses infection rather than helping it. Further tests revealed heightened mitochondrial metabolism consumed more folate needed by T. gondii to make nucleotides—the building blocks of DNA—thus slowing its growth.
“There’s a nutrient competition in which our domesticated microbe is starving the invader microbe,” Pernas stated.
This study is reportedly the first to identify how host cells trigger mitochondrial nutrient competition as part of their defense against infection.
“I think this could apply to any microbe that is dependent on folate to produce that particular nucleotide,” added Pernas. “This would include Plasmodium, which causes malaria, for example. Going forward, we can ask whether folate restriction via mitochondrial metabolism defends against other kinds of infections.”
The findings suggest potential future strategies involving vitamin regimens designed to enhance these natural defenses against infections like toxoplasmosis.
