Neurodegenerative Diseases: What if the Key Lies in the Mitochondria?

Mitochondria, the tiny organelles without which our bodies would be deprived of energy, are gradually revealing their mysteries. In a new study published in Nature Neuroscience, researchers from Inserm and the University of Bordeaux at the NeuroCentre Magendie, in collaboration with researchers from the Université de Moncton in Canada, have for the first time succeeded in establishing a causal link between mitochondrial dysfunction and the cognitive symptoms associated with neurodegenerative diseases.

Thanks to the creation of a specific and unprecedented tool, they succeeded in increasing mitochondrial activity in animal models of neurodegenerative diseases, where they observed an improvement in memory deficit symptoms. While these are only initial results, they open the door to considering mitochondria as a new therapeutic target.

The mitochondrion is a small intracellular organelle that provides the energy needed by the cell to function properly. The brain is one of the most energy-demanding organs, and neurons rely on the energy produced by mitochondria to communicate with one another. Indeed, when mitochondrial activity is impaired, neurons do not have the energy required to function correctly.

Neurodegenerative diseases are characterized by a progressive impairment of neuronal functions leading to the death of brain cells. In Alzheimer’s disease, for example, it has been observed that neuronal degeneration, which precedes cell death, is accompanied by impaired mitochondrial activity. However, due to the lack of suitable tools, it has been difficult in the past to determine whether mitochondrial alterations play a causal role in these conditions or are simply a consequence of the pathophysiological process.

In this new study, researchers from Inserm and the Université de Bordeaux, in collaboration with researchers from the Université de Moncton in Canada, developed for the first time a tool that allows to temporarily stimulate mitochondrial activity. They hypothesized that if this stimulation led to an improvement of symptoms in animals, this would mean that the impairment of mitochondrial activity precedes the loss of neurons in the context of a neurodegenerative disease.

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.

Publication

Potentiation of mitochondrial activity by mitoDREADD-Gs reverses pharmacological and neurodegenerative impairment of cognition

Antonio C. Pagano Zottola ^1,2,3*, Rebeca Martin-Jimenez^4,5,*, Gianluca Lavanco^1,2,6*, Geneviève Hamel-Côté^4,5,*, Carla Ramon-Duaso⁷, Rui S. Rodrigues^1,2, Yamuna Mariani^1,2, Mehtab Khan^4,5, Filippo Drago⁸, Stephanie Jean^4,5, Itziar Bonilla-Del Río^9,10, Daniel Jimenez-Blasco^11,12,13, Jon Egaña-Huguet¹⁴,  Abel Eraso-Pichot^1,2, Sandra Beriain^1,2, Astrid Cannich^1,2, Laura Vidal-Palencia⁷, Rosmara Infantino^1,2, Francisca Julio-Kalajzić^1,2, Doriane Gisquet^1,2, Ania Goncalves^2,15, Inas Al-Younis^4,5, Yann Baussan^4,5, Stephane Duvezin-Caubet^2,16, Anne Devin^2,16, Edgar Soria-Gomez^14,17, Nagore Puente^9,10, Juan P. Bolaños^11,12,13, Pedro Grandes^9,10, Sandrine Pouvreau^1,2, Arnau Busquets-Garcia⁷, Giovanni Marsicano^1,2,#, Luigi Bellocchio^1,2,#, Etienne Hebert-Chatelain^4,5,#

¹ Inserm, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France;
² University of Bordeaux, France;
³ Inserm, U1312 Bordeaux Institute of Oncology, Pessac, France;
⁴ Canada Research Chair in Mitochondrial Signaling and Physiopathology, Canada;
⁵ Department of biology, University of Moncton, Canada;
⁶ Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties of Excellence “G. D’Alessandro”, University of Palermo, Italy;
⁷ Hospital del Mar Medical Research Institute, PRBB, Barcelona, Spain;
⁸ Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy;
⁹ Laboratory of Ultrastructural and Functional Neuroanatomy of the Synapse, Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain;
¹⁰ Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Spain;
¹¹ Institute of Functional Biology and Genomics (IBGF), Universidad de Salamanca, CSIC, Salamanca, Spain;
¹² Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, Salamanca, Spain;
¹³ Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain;
¹⁴ Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country/ “Neuroglia basis of behavioral processes” Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Spain.
¹⁵ CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France;
¹⁶CNRS, IBGC, UMR 5095, Bordeaux, France; ¹⁷ Ikerbasque, Basque Foundation for Science.
^*These authors share first authorship.
^#These authors share senior authorship.
Nature Neuroscience, August 11, 2025
DOI :  10.1038/s41593-025-02032-y / NN-A84112-T

Contacts

Étienne Hébert Chatelain
Professor, Chaire de Recherche du Canada en Signalisation et Physiopathologie Mitochondriales,
Department of Biology, Université de Moncton

Giovanni Marsicano
Inserm Research Director
NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, U1215

Luigi Bellocchio
Inserm Research Scientist
NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, U1215

Press contact

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