Published online 3 March 2010 | Nature | doi:10.1038/news.2010.103


How the cell's powerhouses turn deadly

Mitochondria can trigger a lethal immune response after injuries.

MitochondrionMitochondria, which power cells, can trigger a lethal immune response after trauma.B. LONGCORE / SCIENCE PHOTO LIBRARY

Carl Hauser's patient was dying. A broken pelvis had brought the patient to the hospital, and now it seemed that a severe bacterial infection was killing him. Hauser — a trauma surgeon at the University of Mississippi Medical Center in Jackson — and his colleagues performed test after test, but could not find any sign of infection. Finally, with nothing left to try and time running out, Hauser removed a 30-litre mass of clotted blood. His patient immediately recovered.

It would take Hauser over 15 years to determine why the patient's own damaged tissue nearly killed him.

In a study published today in Nature, Hauser, now at Harvard Medical School, in Boston, Massachusetts, and his colleagues show that molecules produced in mitochondria — the energy-producing structures in cells — escape into the bloodstream during severe trauma, and can fool the immune system into thinking that bacterial invaders are on the loose1.

The immune system's response to this perceived invasion can be deadly. A condition called systemic inflammatory response syndrome (SIRS) can lead to fever, a racing heartbeat, breathing difficulties and, eventually, organ failure. Caused by infection or by trauma alone, SIRS accounts for most of the deaths that occur in hospital intensive-care centres.

"If you twist your ankle and it turns red and swells, that's fine," says Hauser. "If you have such a huge injury that your whole body turns red and swells, you can end up on a ventilator and dialysis with multiple organ failure."

Mistaken identity

The symptoms of trauma-induced SIRS resemble the inflammatory response to severe infection, known as sepsis — but unlike sepsis, there need not be an infection present. As a result, physicians initially thought that a release of bacteria from the gut (rather than bacteria from outside the body) caused trauma-induced SIRS. But subsequent tests showed that this was not the case, and researchers shifted their focus to another possible culprit: the pulverized tissue itself.

Hauser and his colleagues hypothesized that mitochondrial molecules released when tissue is severely damaged could stimulate the immune system in trauma patients who develop SIRS. Because mitochondria are descendants of ancient bacteria that were engulfed and then enslaved by host cells, Hauser reasoned that mitochondrial molecules could resemble bacteria closely enough that they could fool the immune system into thinking an infection has begun.

Mitochondria are normally tucked away inside the cell, separated from the immune system, which detects invaders by exploring cellular surfaces rather than their interiors. But traumatized tissue may release these mitochondrial molecules into the bloodstream, where they could trigger the immune system's sentinels.

To test this, the researchers analysed samples from 15 trauma patients with severe injuries. The patients had thousands of times more mitochondrial DNA in their blood compared with the blood of healthy people. The trauma patients also seemed to have higher levels of mitochondrial peptides in their tissues.


Hauser and his team found that these molecules were able to activate the immune system's normal response to bacteria. Furthermore, when they injected the mitochondrial molecules into rats at concentrations similar to those found in human trauma patients, the animals developed lung and liver damage resembling that observed in human patients with SIRS.


The work is "extraordinary", says Carolyn Calfee, a critical-care physician at the University of California, San Francisco. "We've always wondered why it is that both trauma and sepsis have this similar syndrome," she says. "This opens a whole new set of connections that we hadn't previously realized."

The results suggest that drugs targeting the mitochondrial molecules themselves or early steps in the immune-response pathway could one day be used to treat SIRS. But Hauser cautions that it might not be that simple. Trauma could also activate other pathways that lead to immune-system stimulation, he points out, so simply targeting those that respond to mitochondrial molecules might not be enough to see an effect.

Furthermore, the SIRS response itself could be important for preventing infection during a time when a patient with trauma would be particularly vulnerable, cautions Jérôme Pugin, an intensive-care physician at the University Hospital of Geneva in Switzerland. "Blocking the effects of this mitochondrial DNA could be seen as a good thing because you don't activate the immune system," he says. "On the other hand, maybe it will stop the priming of the immune system for preventing secondary infection." 

  • References

    1. Zhang, Q. et al. Nature 464, 104-107 (2010). | Article
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