Mitochondrial boost reverses dementia symptoms in mice

Could the key to halting dementia lie in the cell’s tiny powerhouses? A team from Inserm, the University of Bordeaux, and the Université de Moncton has provided the first direct evidence that boosting mitochondrial activity can reverse cognitive deficits in animal models of Alzheimer’s disease and frontotemporal dementia. Their work, published in Nature Neuroscience, shows that mitochondria are not just victims of neurodegeneration but active players that can be targeted to restore brain function.

Unlocking the Mitochondrial Connection

Neurons are among the body’s most energy-hungry cells, relying on mitochondria to generate the ATP needed for communication. In neurodegenerative diseases, mitochondrial activity often falters, leaving neurons starved of energy. Until now, scientists could not say whether this was a cause or a consequence of the disease process.

The researchers developed a chemogenetic tool called mitoDREADD-Gs, designed to directly stimulate mitochondrial activity in living brain cells. When activated, it normalized mitochondrial energy production and restored memory performance in mice with dementia-like symptoms.

“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases,” said Giovanni Marsicano, Inserm research director and co-senior author.

How the Tool Works

The mitoDREADD-Gs receptor sits on the outer mitochondrial membrane and triggers a signaling pathway that boosts oxidative phosphorylation. This increases oxygen consumption and mitochondrial membrane potential without changing the number of mitochondria. In the hippocampus, a key memory hub, this extra energy was enough to counteract disease-related deficits.

Key Findings

• MitoDREADD-Gs activation reversed memory loss in mouse models of Alzheimer’s and frontotemporal dementia.
• The effect was linked to stimulation of mitochondrial protein kinase A (PKA) and improved assembly of complex I in the respiratory chain.
• The approach also blocked cannabinoid-induced motor and memory impairments by restoring mitochondrial function.

Testing in Disease Models

In P301S mice, which model early frontotemporal dementia, and APP/PS1 mice, which model Alzheimer’s disease, mitochondrial activity in the hippocampus was significantly reduced. Activating mitoDREADD-Gs restored both energy production and recognition memory performance in these animals.

The intervention did not simply mask symptoms. By reactivating mitochondrial metabolism at a critical disease stage, it addressed an underlying bioenergetic deficit, suggesting that mitochondria could be a viable therapeutic target.

Looking Ahead

While these results come from animal models, the implications are far-reaching. Future work will explore whether sustained mitochondrial stimulation can slow or prevent neuronal loss, and whether similar strategies can be adapted for human treatment. The team also aims to map the precise molecular steps linking mitochondrial G-protein signaling to improved brain function.

“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,” said Étienne Hébert Chatelain, professor at the Université de Moncton and co-senior author.

Journal

Nature Neuroscience, DOI: 10.1038/s41593-025-02032-y