Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice
Nat Neurosci. 2025-08-11; 28(9): 1844-1857
DOI: 10.1038/s41593-025-02032-y
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https://www.bordeaux-neurocampus.fr/12236
Potentiation of mitochondrial function by mitoDREADD-G(s) reverses
pharmacological and neurodegenerative cognitive impairment in mice.
Pagano Zottola AC(#)(1)(2)(3), Martín-Jiménez R(#)(4)(5), Lavanco G(#)(1)(2)(6),
Hamel-Côté G(#)(4)(5), Ramon-Duaso C(7), Rodrigues RS(1)(2), Mariani Y(1)(2),
Khan M(4)(5), Drago F(8), Jean S(4)(5), Río IB(9)(10), Jimenez-Blasco
D(11)(12)(13), Egaña-Huguet J(14), Eraso-Pichot A(1)(2), Beriain S(1)(2),
Cannich A(1)(2), Vidal-Palencia L(7), Infantino R(1)(2), Julio-Kalajzić F(1)(2),
Gisquet D(1)(2), Goncalves A(2)(15), Al-Younis I(4)(5), Baussan Y(4)(5),
Duvezin-Caubet S(2)(16), Devin A(2)(16), Soria-Gomez E(14)(17), Puente N(9)(10),
Bolaños JP(11)(12)(13), Grandes P(9)(10), Pouvreau S(1)(2), Busquets-Garcia
A(7), Marsicano G(18)(19), Bellocchio L(20)(21), Hebert-Chatelain E(22)(23).
Author information:
(1)Endocannabinoids and Neuroadaptation U1215 NeuroCentre Magendie, INSERM,
Bordeaux, France.
(2)University of Bordeaux, Bordeaux, France.
(3)U1312 Bordeaux Institute of Oncology, INSERM, Pessac, France.
(4)Canada Research Chair in Mitochondrial Signaling and Physiopathology,
University of Moncton, Moncton, New Brunswick, Canada.
(5)Department of Biology, University of Moncton, Moncton, New Brunswick, Canada.
(6)Department of Health Promotion, Mother and Child Care, Internal Medicine and
Medical Specialties of Excellence ‘G. D’Alessandro’, University of Palermo,
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, 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)Interdisciplinary Institute for Neuroscience, UMR 5297, CNRS, Bordeaux,
France.
(16)IBGC, UMR 5095, CNRS, Bordeaux, France.
(17)Ikerbasque, Basque Foundation for Science, Leioa, Spain.
(18)Endocannabinoids and Neuroadaptation U1215 NeuroCentre Magendie, INSERM,
Bordeaux, France. .
(19)University of Bordeaux, Bordeaux, France. .
(20)Endocannabinoids and Neuroadaptation U1215 NeuroCentre Magendie, INSERM,
Bordeaux, France. .
(21)University of Bordeaux, Bordeaux, France. .
(22)Canada Research Chair in Mitochondrial Signaling and Physiopathology,
University of Moncton, Moncton, New Brunswick, Canada.
.
(23)Department of Biology, University of Moncton, Moncton, New Brunswick,
Canada. .
(#)Contributed equally
Many brain disorders involve mitochondrial alterations, but owing to the lack of
suitable tools, the causal role of mitochondrial dysfunction in
pathophysiological processes is difficult to establish. Heterotrimeric guanine
nucleotide-binding (G) proteins are key regulators of cell functions, and they
can be found within mitochondria. Therefore, we reasoned that the activation of
stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of
the organelle and possibly compensate for bioenergetic dysfunction. Here, we
show that a mitochondria-targeted recombinant designer receptor exclusively
activated by designer drugs (mitoDREADD-Gs) can acutely trigger
intramitochondrial signaling to increase mitochondrial membrane potential and
oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory
alterations in cannabinoid-treated mice and in two mouse models of Alzheimer’s
disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the
establishment of causal relationships between mitochondria and biological or
disease-related processes and represents an innovative potential therapeutic
approach for disorders associated with mitochondrial impairment.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41593-025-02032-y
PMID: 40790270 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: The authors declare no
competing interests. Ethics and inclusion statement: One or more of the authors
of this paper self-identifies as a member of the LGBTQ+ community.