Scientists discover how cells use a secret weapon to fight off some pathogens

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UCLA 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. You’ve heard that mitochondria are the “powerhouse of the cell.” Now get ready for “mitochondria are the infantry of the cell!” 

UCLA microbiologists have discovered that in addition to producing energy for the cell, mitochondria also work to reduce infections. Their findings, published in Science, show that 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.

Toxoplasma gondii is a parasitic microorganism transmitted by cat feces or undercooked meat that causes toxoplasmosis, an infection that often has no symptoms but can be especially dangerous for immunocompromised people and during pregnancy. In mice, T. gondii infection causes brain changes that make them less wary of cats, and some researchers think that the parasite has a symbiotic relationship with cats, who are not affected by the parasite but benefit from more easily caught prey. Humans may experience some similar changes in the brain, such as being more tolerant of the smell of cat urine. For humans, the far bigger risk is infection of a growing fetus, where it can cause some internal organs to develop improperly. 

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.

“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 corresponding author and UCLA professor of microbiology, immunology and molecular genetics Lena Pernas. “But the reality is that mitochondria are actually a kind of domesticated bacteria that compete with invading pathogens for nutrients.”

Mitochondria evolved a long time ago, when some kind of ancient bacteria entered a cell and established a symbiotic relationship in which it received the nutrients it needed to live, and the cell received the energy it produced through its metabolism. Through this process, called endosymbiosis, the bacteria evolved into mitochondria that exist today. Because they started as bacteria, mitochondria still contain DNA, called mitochondrial DNA, or mtDNA, that is distinct from nuclear 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?” said Pernas. “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.”

This new discovery came about when first author Tânia Catarina Medeiros, a postdoctoral fellow in Pernas’s group at her former institution, the Max Planck Institute for Biology of Ageing, noticed that the amount of mtDNA in mitochondria increased during an infection. By infecting cultured human cells with T. gondii, the researchers found increased production of a protein called ATF4 that regulates gene expression, and that it is activated by stress such as invading microbes. ATF4 led to an increase in the amount of mtDNA, but it also indicated that the cell was able to detect the presence of the pathogen, which activated a response that increased mitochondrial metabolism. The cell was able to do this because it could actually detect the proteins the parasite secretes.

“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,’” said Pernas.

To find out if the parasites were benefiting from the increased mitochondrial metabolism, the researchers deleted ATF4 and found that the parasites did better when mitochondrial metabolism was unaltered. This showed that the increased metabolism, which was a response to infection, was actually working to suppress the infection.

Further investigation revealed that the amped up mitochondrial metabolism consumed more folate, which the parasite needs for the special way it makes nucleotides, the basic building blocks of DNA. Without the ability to make this critical building block, the T. gondii parasites grew more slowly.

“There’s a nutrient competition in which our domesticated microbe is starving the invader microbe,” said Pernas.

The study is the first to identify a host pathway that activates mitochondrial nutrient competition, and to show that it plays a role in preventing infections.

“I think this could apply to any microbe that is dependent on folate to produce that particular nucleotide,” said 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.”

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