Fireworks shed light on the function of mitochondria

Tiny factories float in our cells and supply them with almost all the energy they need: the mitochondria. Their effectiveness decreases as we get older, but also as we encounter many diseases such as diabetes, cancer or Parkinson’s. This is why scientists are becoming increasingly interested in how they work. At EPFL, a team has developed a protocol to measure their activity live in live animals. Described in Natural chemical biology, the method is based on the molecule responsible for the bioluminescence of the firefly. In the most literal sense of the word, this study sheds light on how mitochondria work.

Mitochondria are almost like cells in the cell. Like their host, they have a membrane that protects their genetic material and, most importantly, exchanges filters with the outside. The difference in electrical charge between the inside and outside of the mitochondria, called ‘membrane potential’, allows certain molecules to pass through while other ramain is at bay.

If between the two poles of a used electric battery, the membrane potential of the mitochondria can sometimes drop. For scientists, this is an inconceivable indication that its functions are limited.

We know how to measure the phenomenon on cultured cells. But until now, you could not really see it on live animals. “Cell cultures are not very effective at studying diseases associated with mitochondria,” explains Elena Goun, professor at EPFL and lead author of the article, “Cancer and diabetes involve complex exchanges between different types of cells, so we need animal models. “

Elena Goun and her colleagues have found a way to study the phenomenon in live mice. They use genetically modified animals to express luciferase – an enzyme that produces light when combined with another compound called luciferin. This is how fireflies sometimes light up our summer evenings.

Scientists have developed two molecules that, when injected into the rodent, pass into the mitochondria, where they activate a chemical reaction. The mitochondria then produce luciferin and release it. Luciferin combines with luciferase in the cells of the mice and produces light.

“In a completely darkened room, you can see the mice glowing, just like fireflies,” says Elena Goun.

Researchers only need to measure light intensity to get a clear picture of how well the mitochondria are functioning. If they function less well, their membrane leaves less chemical compounds. The production of luciferin decreases, and therefore also the lightness.

To demonstrate the potential of their method, the researchers performed several experiments. For example, they found that older rodents produce significantly less light. This drop in light reflects a decrease in the activity of mitochondria – their membrane potential is much lower than in younger rodents. We know that age causes a decrease in the activity of mitochondria, but this is the first time that the phenomenon has been measured directly in living animals.

The team also tested a chemical known to rejuvenate mitochondria: nicotinamide riboside. This molecule is non-toxic and commercially available as a dietary supplement. Mice given this compound produced more light, a sign of increased mitochondrial activity.

The researchers were also able to measure the same phenomenon in animal models of cancer. This can be of great help for research into anti-drug drugs. In addition, they also successfully demonstrate monitoring of mitochondria membrane potential in cells of brown adipose tissue, rich in mitochondria. Its stimulation could help cure certain forms of obesity.

The method described by Elena Goun is primarily intended for scientists who want to better understand the role of mitochondria and who need an animal model. The field of application is wide: diabetes, oncology, aging, nutrition, neurogenerative diseases … “Our process can measure varying degrees of mitochondrial activity, and not just an on / off signal,” explains Elena Goun. “It’s extremely sensitive – much more than a PET scan – affordable and easy to implement.