Reviving memories through the activation of brain mitochondria.

In a groundbreaking discovery, French scientists from Inserm and Bordeaux University have developed a genetic tool called mitoDREADD-Gs that could revolutionize the treatment of dementia and other neurodegenerative diseases. This tool, which selectively activates mitochondrial G protein signaling in brain cells, boosts energy production and has shown promising results in reversing memory loss in dementia mouse models.

Until now, it was widely believed that energy damage was a late consequence of neurodegeneration, not its origin. However, this new finding establishes a causal link between mitochondrial dysfunction and dementia symptoms, suggesting that impaired mitochondrial activity may be a root cause of neurodegeneration rather than just a downstream effect.

The mitoDREADD-Gs system works by inserting a designer receptor into the mitochondrial membrane of brain cells. When activated by a harmless lab-made drug (clozapine-N-oxide, or CNO), this receptor activates G proteins directly inside mitochondria, boosting energy production through enhanced oxidative phosphorylation. This activation effectively reactivates the mitochondria and increases their output.

In experiments with mice, this targeted mitochondrial stimulation rapidly reversed memory impairments caused by THC-induced mitochondrial dysfunction. Moreover, in more complex models of neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia, a single dose of the CNO drug activating mitoDREADD-Gs significantly improved memory performance, as shown in behavioral tests. The tool provides precision control at a subcellular level, selectively enhancing mitochondrial function without broadly affecting the entire cell.

This breakthrough offers a promising avenue for precision energy treatments, potentially enabling therapies that restore neuronal function by directly recharging brain cell “batteries” rather than broadly targeting cells or tissues. This approach could lead to the development of new therapeutic targets that specifically address mitochondrial deficits, possibly delaying or preventing neuronal loss in neurodegenerative diseases.

However, it's important to note that the clinical application of the study's findings is still distant due to temporary improvements and the need for continuous or recurrent stimulation, posing technical and ethical challenges for human use. Nevertheless, the future of brain medicine may not solely lie in genetics or pharmacology, but in redesigning cellular energy.

The discovery challenges decades of scientific consensus about the role of mitochondria in neurodegenerative diseases. In the new paradigm, mitochondria are central actors in brain aging and neurodegenerative diseases, and their function can be altered and restored with precision. The finding was published in Nature Neuroscience, opening up a new therapeutic pathway for disorders like Alzheimer's, where cerebral energetic stimulation could slow cognitive decline if detected and treated in early stages.

Moreover, the energetic approach could extend beyond dementia to depression, multiple sclerosis, and developmental disorders, which have also shown links to mitochondrial dysfunction. Memory ultimately depends on energy, and memories are sustained by precise energy flows, challenging our understanding of brain aging. The shift in perspective suggests that cognitive decline could be stopped - and even reversed - if brain energy function is restored in time.

In one of the most striking tests in the study, mice with artificially deteriorated memory through THC administration were treated with mitoDREADD-Gs. After activation, the mice recovered their memory in a few hours. Similarly, the most promising results came from genetic models of human neurodegenerative diseases, where a single activating dose was enough to measurably improve memory. However, it's worth noting that human brains with advanced dementia have irreversible loss of synaptic connections, which would limit the restorative effects of the treatment.

In conclusion, the mitoDREADD-Gs tool offers a promising new approach to treating dementia and other neurodegenerative diseases by selectively activating mitochondrial G protein signaling in brain cells, boosting energy production, and reversing memory loss. The findings challenge decades of scientific consensus and open up a new therapeutic pathway for disorders like Alzheimer's, where cerebral energetic stimulation could slow cognitive decline if detected and treated in early stages.