Mitochondria, the tiny organelles without which our bodies would be deprived of energy, are gradually revealing their mysteries. In a new study published in Nature Neuroscience, researchers from Inserm and the University of Bordeaux at the NeuroCentre Magendie, in collaboration with researchers from the Université de Moncton in Canada, have for the first time succeeded in establishing a causal link between mitochondrial dysfunction and the cognitive symptoms associated with neurodegenerative diseases.
Thanks to the creation of a specific and unprecedented tool, they succeeded in increasing mitochondrial activity in animal models of neurodegenerative diseases, where they observed an improvement in memory deficit symptoms. While these are only initial results, they open the door to considering mitochondria as a new therapeutic target.
The mitochondrion is a small intracellular organelle that provides the energy needed by the cell to function properly. The brain is one of the most energy-demanding organs, and neurons rely on the energy produced by mitochondria to communicate with one another. Indeed, when mitochondrial activity is impaired, neurons do not have the energy required to function correctly.
Neurodegenerative diseases are characterized by a progressive impairment of neuronal functions leading to the death of brain cells. In Alzheimer's disease, for example, it has been observed that neuronal degeneration, which precedes cell death, is accompanied by impaired mitochondrial activity. However, due to the lack of suitable tools, it has been difficult in the past to determine whether mitochondrial alterations play a causal role in these conditions or are simply a consequence of the pathophysiological process.
In this new study, researchers from Inserm and the Université de Bordeaux, in collaboration with researchers from the Université de Moncton in Canada, developed for the first time a tool that allows to temporarily stimulate mitochondrial activity. They hypothesized that if this stimulation led to an improvement of symptoms in animals, this would mean that the impairment of mitochondrial activity precedes the loss of neurons in the context of a neurodegenerative disease.
In previous studies, the research teams already described the specific role of G proteins [1] in the modulation of mitochondrial activity in the brain. In the present paper, the researchers succeeded in generating an artificial receptor, called mitoDreadd-Gs, able to activate G proteins directly in the mitochondria, thereby stimulating mitochondrial activity. The stimulation of mitoDreadd-Gs in the brain led to the normalisation of both mitochondrial activity and memory performance of dementia mouse models.
"This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration", explains Giovanni Marsicano, Inserm research director and co-senior author of the study.
"These results will need to be extended, but they allow us to better understand the important role of mitochondria in the proper functioning of our brain. Ultimately, the tool we developed could help us identify the molecular and cellular mechanisms responsible for dementia and facilitate the development of effective therapeutic targets", explains Étienne Hébert Chatelain, professor at the Université de Moncton and co-senior author of the study.
"Our work now consists of trying to measure the effects of continuous stimulation of mitochondrial activity to see whether it impacts the symptoms of neurodegenerative diseases and, ultimately, delays neuronal loss or even prevents it if mitochondrial activity is restored," added Luigi Bellocchio, Inserm researcher and co-senior author of the study.
[1] G-proteins have the specific role of enabling the transfer of information within cells.
