Scientists have developed a novel tool that can boost energy production in brain cells and reverse memory loss in mouse models of dementia. The study, published in Nature Neuroscience, suggests that low mitochondrial activity may be a direct cause of cognitive decline in neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia. By activating this new tool in the hippocampus, the part of the brain involved in memory, researchers were able to restore recognition memory in mice with early-stage disease-related impairments.
The study was led by researchers from Inserm and the University of Bordeaux at the NeuroCentre Magendie in France, in collaboration with the Université de Moncton in Canada and several European neuroscience centers. The team’s goal was to explore whether impaired mitochondrial function plays a causal role in the cognitive symptoms seen in brain disorders. Mitochondria, often described as the cell’s power plants, are responsible for producing the energy needed for a wide range of cellular functions, including those in neurons.
Previous research has repeatedly observed mitochondrial deficits in conditions such as Parkinson’s disease, Alzheimer’s, and frontotemporal dementia. But these associations have been mostly correlational. It remained unclear whether these energy impairments were a root cause of cognitive problems or a secondary effect of other disease mechanisms. One of the main reasons for this uncertainty was the lack of tools to directly and selectively increase mitochondrial activity in living brain tissue.
“Together with my collaborators, I have long been dedicated to investigating the mechanisms by which mitochondria (these microscopic energy powerhouses) support optimal brain function,” explained study author Etienne Hébert Chatelain, an associate professor of biology at the Université de Moncton and Canada Research Chair in Mitochondrial Signaling.
“Mitochondria generate the energy required for cellular processes, and their role is particularly critical in the brain, which is the most energy-demanding organ in the human body. Our previous research has demonstrated that even subtle alterations in mitochondrial activity can significantly impact key cognitive functions, such as learning and memory.”
“Furthermore, it has been hypothesized that mitochondrial dysfunction in the brain may contribute to the onset and progression of various neurodegenerative disorders. Motivated by these insights, we sought to develop a novel tool capable of enhancing mitochondrial activity. Our aim was to deepen our understanding of the role these organelles play in maintaining normal brain function and to explore the potential of mitigating or slowing the development of certain neurodegenerative diseases.”
The researchers developed a novel tool using an approach called chemogenetics, which allows specific cell functions to be controlled by synthetic compounds. In chemogenetics, receptors are genetically engineered so they no longer respond to the body’s natural molecules but can instead be activated by an otherwise inert chemical. In this case, the team created a receptor called mitoDREADD-Gs. DREADD stands for “Designer Receptor Exclusively Activated by Designer Drug,” and these receptors are designed to respond only to a lab-made compound called clozapine-N-oxide.
MitoDREADD-Gs was engineered to localize to mitochondria, the energy-producing structures inside cells. When clozapine-N-oxide is administered, it activates the receptor, triggering internal signaling pathways that boost mitochondrial activity. The researchers first confirmed that the Gs protein—a key signaling molecule—exists within mitochondria. They then built a version of the DREADD receptor that could activate Gs signaling specifically inside the organelle.
When mitoDREADD-Gs was activated in cultured cells, the researchers observed a clear increase in mitochondrial function. Membrane potential rose, oxygen consumption increased, and overall energy production improved. These effects were only seen with the mitochondrial-targeted version of the receptor, not with a version that remained outside the organelle. This provided initial evidence that stimulating mitochondrial signaling directly could enhance energy metabolism.
“Several molecules or treatments are known to reduce mitochondrial activity,” Chatelain told PsyPost. “What makes mitoDREADD-Gs particularly exciting is that it’s one of the very few tools that can increase mitochondrial activity in a targeted and controlled way. This discovery was a major breakthrough, as it opens up new possibilities for studying and potentially improving how cells produce energy, especially in the brain.”
Next, they tested whether this mitochondrial activation could counteract memory impairments. To do this, they used mouse models of frontotemporal dementia (P301S mice) and Alzheimer’s disease (APP/PS1 mice). Both models show early memory deficits that resemble symptoms in human patients, along with reduced mitochondrial activity in the hippocampus.
The researchers delivered mitoDREADD-Gs into the hippocampus of these mice using viral vectors. After several weeks, they tested memory using the novel object recognition task, a widely used behavioral test in which mice typically spend more time exploring a new object than a familiar one. Mice with dementia-like pathology performed poorly on this task, indicating memory impairment. But when mitoDREADD-Gs was activated shortly after learning, their memory performance improved significantly.
These effects were not observed when a non-mitochondrial version of the receptor was used. The reversal of memory loss required activation of mitochondrial Gs signaling and downstream stimulation of protein kinase A (PKA), a key regulator of mitochondrial function. The researchers further showed that activating mitoDREADD-Gs increased the phosphorylation of specific mitochondrial proteins and enhanced the assembly of respiratory complexes involved in energy production.
In a separate set of experiments, the team also demonstrated that mitoDREADD-Gs could reverse memory and motor impairments induced by the cannabinoid THC. These effects are known to involve inhibition of mitochondrial function in brain circuits. When mitoDREADD-Gs was activated in hippocampal or striatal neurons, it prevented THC-induced memory impairments and cataleptic responses. These findings provided additional support for the idea that the tool can counteract behavioral deficits linked to mitochondrial inhibition.
Importantly, the memory-rescuing effects of mitoDREADD-Gs in dementia models occurred even when the underlying pathology, such as tau aggregation or amyloid buildup, remained unchanged. This suggests that at least some of the cognitive symptoms in neurodegenerative diseases may stem from modifiable mitochondrial dysfunction rather than irreversible structural damage.
“Our study shows that when mitochondria (the tiny structures in our cells that produce energy) don’t work properly, they can directly cause some of the symptoms seen in dementia,” Chatelain explained. “In fact, we found a clear connection between low mitochondrial activity and memory problems in two different mouse models of dementia. To explore this further, we created a new tool called mitoDREADD-Gs. When this tool is activated in the brain, it boosts mitochondrial activity. Remarkably, turning it on in the hippocampus (a part of the brain that plays a key role in memory) was enough to reverse memory loss in these mice.”
“Why does this matter? Because the brain needs a huge amount of energy to function properly, and problems with energy production are linked to diseases like Alzheimer’s and other forms of dementia. By having a tool that can safely and specifically boost energy production in brain cells, researchers can explore new ways to improve memory and slow down the progression of neurodegenerative diseases. It’s a major step forward in understanding and potentially treating conditions that affect millions of people.”
While the findings offer evidence that mitochondrial dysfunction can directly impair memory, several questions remain. The study was conducted in mice, and although these animal models mimic aspects of human disease, they do not capture its full complexity. Whether similar effects would be observed in human brain tissue or in living patients is currently unknown.
Another limitation is that the mitoDREADD-Gs tool is based on gene therapy and chemogenetics, which are not yet approved for widespread clinical use. The delivery of the receptor to specific brain regions and cell types would be challenging in a therapeutic context.
“To test our tool mitoDREADD-Gs, we had to use a surgical method to inject a virus into the brains of mice,” Chatelain noted. “This allowed the tool to be activated in specific brain areas. While this worked well in our study, it’s not a realistic option for humans right now because the procedure is very invasive. That’s why we’re now looking for safer and more practical ways to use what we’ve learned to help develop future treatments for dementia.”
Nonetheless, the tool provides a powerful method for dissecting the biological role of mitochondria in brain function and for testing experimental treatments in animal models.
“In our study, we also looked closely at what happens inside brain cells when mitoDREADD-Gs is activated,” Chatelain said. “We were able to identify the chain of molecular events that leads to increased mitochondrial activity—and ultimately, better memory. We’re now working to find out which types of brain cells are most affected by these changes. This will help us understand at what stage of dementia these effects could be most useful, and whether it’s possible to reverse symptoms depending on how far the disease has progressed.
“I would like you to acknowledge the great work of my co-corresponding authors Luigi Bellocchio and Giovanni Marsicano along with all other co-authors,” he added.
The study, “Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice,” was authored by Antonio C. Pagano Zottola, Rebeca Martín-Jiménez, Gianluca Lavanco, Geneviève Hamel-Côté, Carla Ramon-Duaso, Rui S. Rodrigues, Yamuna Mariani, Mehtab Khan, Filippo Drago, Stephanie Jean, Itziar Bonilla-Del Río, Daniel Jimenez-Blasco, Jon Egaña-Huguet, Abel Eraso-Pichot, Sandra Beriain, Astrid Cannich, Laura Vidal-Palencia, Rosmara Infantino, Francisca Julio-Kalajzić, Doriane Gisquet, Ania Goncalves, Inas Al-Younis, Yann Baussan, Stephane Duvezin-Caubet, Anne Devin, Edgar Soria-Gomez, Nagore Puente, Juan P. Bolaños, Pedro Grandes, Sandrine Pouvreau, Arnau Busquets-Garcia, Giovanni Marsicano, Luigi Bellocchio, and Etienne Hebert-Chatelain.
