Small plants float inside our cells and give them nearly all the energy they need: mitochondria. Their effectiveness decreases as we age, but also when we face many diseases such as diabetes, cancer or Parkinson̵7;s. This is why scientists are becoming increasingly interested in how they work. At EPFL, a team developed a protocol to measure their activity in living animals. Describe what Natural Chemistry BiologyThis method relies on the molecule responsible for firefly bioluminescence. In the literal sense of the word, this study sheds light on how mitochondria work.
Mitochondria are almost like cells inside a cell. Like their host, they have a membrane that protects their genetic material and, above all, a filter for external exchange. The difference in charge between the inside and outside of the mitochondria, called the ‘membrane potential’, allows some molecules to pass, while others are inactive.
As between the two poles of a used battery, the membrane voltage of the mitochondria can sometimes drop. For scientists, this is an unmistakable clue that its functions are in decline.
We know how to measure this phenomenon on cell cultures. But so far, you really couldn’t see it on live animals. “Cell culture is not very effective at studying mitochondrial diseases, so we need animal models,” explains Elena Goun, professor at EPFL and lead author of the paper. .
Elena Goun and her colleagues have found a way to study this phenomenon in live mice. They used genetically engineered 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 rodents, enter the mitochondria, where they trigger a chemical reaction. The mitochondria then produce luciferin and push it out. Luciferin binds with luciferase in mouse cells and produces light.
Elena Goun said: “In a completely dark room you can see glowing rats, like fireflies.
Researchers only need to measure light intensity to get a clear picture of how well the mitochondria are working. When they are ineffective, their membranes contain less chemical compounds. The production of luciferin is reduced and thus brightness is also reduced.
To demonstrate the potential of their method, the researchers performed a number of experiments. For example, they observed that older rodents produced significantly less light. This light drop reflects a decrease in mitochondrial activity – their membrane potential is much lower than that of younger rodents. We know that age reduces mitochondrial activity, but this is the first time that this phenomenon has been directly measured in live animals.
The team also tested a chemical known to rejuvenate the mitochondria: nicotinamide riboside. This molecule is non-toxic and is commercially available as a supplement. Rats given the compound produced more light, an indication of increased mitochondrial activity.
Researchers were also able to measure similar phenomena on animal models of cancer. This could be of great help for anti-cancer drug research. In addition, they have also demonstrated successful monitoring of the mitochondrial membrane potential in mitochondrial, brown adipose tissue cells. Its stimulation can help cure some 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 animal modeling. The field of application is very wide: diabetes, cancer, aging, nutrition, neurodegenerative diseases … “Our process can measure different levels of mitochondrial activity. it’s just an on / off signal, “explained Elena Goun. “It’s incredibly responsive – much more so than a PET scan – it’s affordable and easy to do.
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Bazhin, AA, Sinisi, R., De Marchi, U. et al. A bioluminescent probe for longitudinal monitoring of the mitochondrial membrane potential. Nat Chem Biol (Year 2020). doi.org/10.1038/s41589-020-0602-1
Provided by Ecole Polytechnique Federale de Lausanne
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