How Recharging the Brain’s “Batteries” Restored Lost Memory

Mitochondria are tiny structures inside our cells that supply the energy our bodies need to survive, and scientists are steadily uncovering more about how they work. A new study in Nature Neuroscience, led by researchers at Inserm and the University of Bordeaux’s NeuroCentre Magendie in partnership with the Université de Moncton in Canada, has for the first time shown a direct cause-and-effect relationship between malfunctioning mitochondria and the cognitive problems linked to neurodegenerative diseases.

Using a newly developed, highly specialized tool, the team was able to boost mitochondrial activity in animal models of neurodegenerative disorders. This intervention led to noticeable improvements in memory deficits. Although these findings are preliminary, they point to mitochondria as a promising focus for future therapies.

Why Brain Cells Depend on Mitochondria

A mitochondrion is a small structure within cells that generates the energy needed for normal cellular activity. The brain consumes an enormous amount of energy, and its neurons depend on the power produced by mitochondria to send signals to one another. When mitochondrial performance falters, neurons lose the energy required to work properly.

Neurodegenerative diseases gradually disrupt how neurons function and ultimately lead to their death. In Alzheimer’s disease, for instance, the decline of neurons before cell death occurs is often accompanied by reduced mitochondrial activity. Until now, the lack of effective tools has made it difficult to determine whether this mitochondrial decline actually contributes to the disease process or merely results from it.

A Groundbreaking Experimental Tool

In this latest research, scientists from Inserm and the University of Bordeaux, working with colleagues at the Université de Moncton, created a novel method to temporarily increase mitochondrial activity. They reasoned that if stimulating mitochondria improved symptoms in animals, it would indicate that the loss of mitochondrial function happens before neurons die in neurodegenerative disease.

Targeting G Proteins to Restore Brain Function

In previous studies, the research teams already described the specific role of G proteins^[1] in the modulation of mitochondrial activity in the brain. In the present paper, the researchers succeeded in generating an artificial receptor, called mitoDreadd-Gs, able to activate G proteins directly in the mitochondria, thereby stimulating mitochondrial activity. The stimulation of mitoDreadd-Gs in the brain led to the normalisation of both mitochondrial activity and memory performance of dementia mouse models.

“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.

Looking Ahead to New Therapies

“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.

“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.

Notes

1. G-proteins have the specific role of enabling the transfer of information within cells.

Reference: “Potentiation of mitochondrial function by mitoDREADD-G_s reverses pharmacological and neurodegenerative cognitive impairment in mice” 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, 11 August 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-02032-y

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