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

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. Activation of Gs signaling at mitochondria by mitoDREADD-Gs increases mitochondrial metabolism, leading to better memory in mouse models of dementia, directly linking brain mitochondrial deficits to cognitive symptoms of neurodegenerative diseases.