Sepsis Therapy May Come from the Sea

An alternative oxidase from a sea squirt, Ciona intestinalis, can prevent bacterial sepsis. [Howard Jacobs/University of Helsinki]

Researchers have known that mitochondrial alternative oxidase (AOX) from a marine invertebrate, the sea squirt, works as a safety valve for stressed mitochondria. This property enables it to stop the runaway inflammatory process that leads to multiple organ failure and eventual death in bacterial sepsis.

Now Marten Szibor, Ph.D., and Howard Jacobs, Ph.D., from the Institute of Biotechnology, University of Helsinki, report that mitochondria also participate in the signaling process that leads to the activation of macrophages, which are one of the front-line components of the immune system. When stimulated by lipopolysaccharide, a common chemical constituent of the outer envelope of bacteria, they undergo a reprogramming of metabolism. Mitochondria switch to the production of oxygen radicals, alerting the body to the threat. Sepsis occurs when the process spins out of control.

“The mitochondrial switch initiates a cascade of proinflammatory signals. But the process can be counteracted by various different treatments which limit oxygen radical production,” says Dr. Jacobs.

The team published its study (“Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages”) in Cell.

For a number of years, Dr. Jacobs' group has been studying the properties of the mitochondrial AOX. Together with collaborators, they have now demonstrated its potential to combat the runaway inflammatory process that leads to multiple organ failure and eventual death, in bacterial sepsis.

AOX is not found naturally in mammals, so the group has turned to the sea squirt Ciona as a source. It turns out that the AOX gene from this species is fully functional when expressed in human cells or model organisms like fruit flies or mice. AOX bypasses the mitochondrial energy system when it isn't fully functional due to chemical damage, toxins, genetic errors, or overload. Under normal conditions, it seems to have no effect on cellular processes, yet it acts as a kind of safety valve when the mitochondria become stressed. So AOX is effective in blocking sepsis, because it relieves the buildup of metabolic intermediates that otherwise lead to excessive oxygen radical production.

“More people die of sepsis than of cancer. So anything that improves our understanding of how it develops and how to fight it, should have dramatic life-saving implications. It's obviously far too soon to say whether AOX could be used as an actual therapy for sepsis, and if so, how best to deliver it. But equally, using the knowledge obtained in this project may lead to simpler, 'chemical' ways of producing a similar outcome and saving many lives,” according to Dr. Jacobs.