A team from Inserm (Institut national de la santé et de la recherche médicale) and the Université de Bordeaux, working with collaborators at the Université de Moncton in Canada, has developed a molecular tool that could change how scientists approach neurodegenerative disease treatment. Their study, “Potentiation of mitochondrial activity by mitoDREADD-Gs reverses pharmacological and neurodegenerative impairment of cognition,” published in Nature Neuroscience, describes how targeted stimulation of mitochondria in the brain restored memory performance in animal models of Alzheimer’s disease and frontotemporal dementia.
The brain, one of the most energy-hungry organs, depends on mitochondrial activity to power neuron-to-neuron communication. In Alzheimer’s disease, mitochondrial impairment precedes cell death, but until now, it was unclear whether this dysfunction was a cause or a consequence of disease progression.
The newly developed tool, mitoDREADD-Gs, is a mitochondria-targeted version of a designer receptor exclusively activated by designer drugs. By activating a stimulatory G protein (Gs) directly within mitochondria, the receptor boosts mitochondrial membrane potential and oxygen consumption—hallmarks of increased energy production. “In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer’s disease and frontotemporal dementia,” the authors wrote.
In previous work, the team showed that certain G-protein signaling pathways could suppress mitochondrial function, contributing to cognitive deficits. This new study flips that script—enhancing G-protein signaling within mitochondria to restore function and cognition.
“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,” said Giovanni Marsicano, PhD, Inserm research director and co-senior author.
“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,” shared co-senior author Étienne Hébert Chatelain, PhD, professor at the Université de Moncton and co-senior author of the study. She added, “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.”
The team’s next steps include testing whether sustained stimulation of mitochondrial activity could delay—or even prevent—neuronal loss in disease models. “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, PhD, Inserm researcher and co-senior author of the study. If successful, such work could pave the way for mitochondrial-targeted therapies across a range of neurodegenerative and mitochondrial-related conditions.
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