Sometimes the problem starts before brain cells die.

Researchers from Inserm and the University of Bordeaux at the NeuroCentre Magendie, working with scientists at the Université de Moncton in Canada, say they have shown for the first time a direct cause-and-effect link between faulty mitochondrial activity and cognitive symptoms linked to neurodegenerative disease.

The study, published in Nature Neuroscience, focused on mitochondria, the structures inside cells that generate energy. In the brain, that energy helps neurons communicate and form memories.

The team developed a tool that can temporarily stimulate mitochondrial activity in animal models of neurodegenerative disease. In the 2025 study, they built an artificial receptor called mitoDreadd-Gs, designed to activate G proteins directly inside mitochondria and stimulate mitochondrial activity.

When mitoDreadd-Gs was activated in the brain, mitochondrial activity returned to normal levels. Memory performance also improved in mouse models of dementia.

The researchers said the findings suggest mitochondrial impairment can come before neuron loss and contribute directly to cognitive decline.

“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration,” explains Giovanni Marsicano, Inserm research director and co-senior author of the study.

Neurodegenerative diseases involve a gradual decline in neuronal function, followed by the death of brain cells. In Alzheimer’s disease, researchers have long observed mitochondrial problems alongside neuronal degeneration, often before cells die, but it has been difficult to determine if those problems were a cause or a result of the disease process.

The researchers said their results do not mean a treatment is ready for patients. The work was carried out in animal models, and they said much more research is needed to find out if similar approaches could be safe, durable and effective in humans.

“These results will need to be extended, but they allow us to better understand the important role of mitochondria in the proper functioning of our brain. Ultimately, the tool we developed could help us identify the molecular and cellular mechanisms responsible for dementia and facilitate the development of effective therapeutic targets,” explains Étienne Hébert Chatelain, professor at the Université de Moncton and co-senior author of the study.

The next question for the team is what happens with longer-term stimulation of mitochondrial activity, and if restoring that function could affect symptoms of neurodegenerative diseases, delay neuronal loss or prevent it.

“Our work now consists of trying to measure the effects of continuous stimulation of mitochondrial activity to see whether it impacts the symptoms of neurodegenerative diseases and, ultimately, delays neuronal loss or even prevents it if mitochondrial activity is restored,” added Luigi Bellocchio, Inserm researcher and co-senior author of the study.

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