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<p>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 (G<sub>s</sub>) 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-G<sub>s</sub>) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-G<sub>s</sub> abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer’s disease and frontotemporal dementia. Thus, mitoDREADD-G<sub>s</sub> 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.</p>

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Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • 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,
  • Etienne Hebert-Chatelain

摘要

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.