Are we at a turning point regarding the Alzheimer's disease ? New drugs, new screening tests, vaccine candidates (this is the cover story) of the new issue of Science and Future)… The fight against this neurodegenerative disease and other dementias seems to have entered a new dynamic. In particular because we understand better and better the mechanisms involved, such as energy dysfunctions. Abnormalities in energy generation at the level of mitochondria, which provide most of the energy used by cells, have long been observed in Alzheimer's disease. To the point that this energy production capacity is now considered a good indicator of risk to develop it. A new study, published on August 11, 2025 in Nature Neuroscience, even suggests that these mitochondrial defects would be one of the causes at the origin of the disease. Science and Future asked one of the study's directors, Etienne Hébert Chatelain, professor of mitochondrial signaling at the University of Moncton in Canada.
“Could repairing these mitochondrial problems correct memory defects?”
Sciences and Future:What was the initial hypothesis of your study?
Etienne Hébert Chatelain:Mitochondrial dysfunction has been observed for decades in both in vitro animal models and post-mortem tissue samples from Alzheimer's patients. In the field of mitochondrial research, a hypothesis had therefore emerged: mitochondria could be the cause of neurodegenerative diseases. In other words, the observed defects were not simply consequences of the disease, but one of its causes. The challenge was to prove this, to show that repairing these mitochondrial problems could correct the memory defects characteristic of this disease and other dementias.
And how can we repair these mitochondrial problems?
We focused on G proteins, small signaling relays inside cells. These messengers are coupled to receptors that ensure communication between the outside and the inside of the cell. These receptors are activated when they come into contact with certain proteins, which causes these G proteins to be released inside the cell, activating signaling cascades. These G proteins can interact with different elements in the cell as needed, depending on the initial message. We discovered that some of them are also present in the mitochondria, where they can either inhibit their activity or, conversely, stimulate it.
“Mitochondrion is involved in metabolic diseases, cancer, kidney or liver damage…”
So you were able to use these G proteins to stimulate mitochondria?
That's right. To do this, we modified one of these receptors so that it anchors to the surface of mitochondria. We chose a receptor that was already modified so that it was coupled only to a specific type of G protein, known to stimulate mitochondrial activity. This receptor is only activated upon contact with a small molecule that is known to have no other effect in the cell. Thanks to this system, we can control the activation of G proteins directly inside the mitochondria, and therefore stimulate oxidative phosphorylation at will—that is, the capacity of mitochondria to consume oxygen to produce ATP, and therefore energy. This tool makes it possible to activate mitochondria in a targeted and timely manner.
And what happens when we activate the mitochondria?
We tested this in animal models of dementia and Alzheimer's disease. We observed a significant improvement in their memory, which shows that the corrected mitochondrial dysfunctions play a direct role in these disorders. This establishes a causal link: mitochondrial defects are at least partly responsible for the cognitive defects in dementia.
Now that you have shown this causal link, what is the next step?
This tool allows us to better understand what happens at the beginning of the pathology, to decipher its mechanisms. From now on, we want to study the entire signaling pathway activated after the release of G proteins in the mitochondria, in order to identify the key steps that can be corrected by this activation. The objective is then to find molecules that could block these processes without going through the modified receptor, since it cannot be used in humans. This opens the way to other potential therapeutic strategies against the disease.
Mitochondrial defects are also observed in other diseases. Could this tool be used in these contexts?
Indeed, mitochondria are involved in metabolic diseases, cancer, kidney and liver damage, etc. All organs with high energy demands depend on the proper functioning of mitochondria. This tool could therefore be applied to a wide range of pathologies, both to better understand their mechanisms and to pave the way for new potential treatments.
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