| First Author | Pagano Zottola AC | Year | 2025 |
| Journal | Nat Neurosci | Volume | 28 |
| Issue | 9 | Pages | 1844-1857 |
| PubMed ID | 40790270 | Mgi Jnum | J:386172 |
| Mgi Id | MGI:8279212 | Doi | 10.1038/s41593-025-02032-y |
| Citation | Pagano Zottola AC, et al. (2025) Potentiation of mitochondrial function by mitoDREADD-G(s) reverses pharmacological and neurodegenerative cognitive impairment in mice. Nat Neurosci 28(9):1844-1857 |
| abstractText | 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(s)) 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(s)) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-G(s) abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-G(s) 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. |
