Unraveling the Mystery: How Free Radicals May Trigger Dementia
In a groundbreaking study, researchers have uncovered a potential link between free radicals generated in a specific area of the brain and the development of dementia. This discovery, published in Nature Metabolism, offers a new perspective on neurodegenerative disorders and opens up exciting possibilities for treatment.
The study, led by Dr. Anna Orr and Dr. Adam Orr, focused on non-neuronal brain cells called astrocytes. These cells, often overlooked, may play a crucial role in the progression of dementia. The researchers found that blocking a specific site in astrocytes' mitochondria reduced brain inflammation and protected neurons, suggesting a novel therapeutic approach.
Dr. Anna Orr expressed her excitement about the potential impact of this research, stating, "We now have the ability to target precise mechanisms and address the exact sites relevant to the disease." This targeted approach could revolutionize the way we treat neurodegenerative disorders.
The Role of Mitochondria and ROS
Mitochondria, often referred to as the powerhouses of the cell, are responsible for generating energy from food. However, in the process, they also release reactive oxygen species (ROS), which can be harmful when produced excessively.
Decades of research have implicated mitochondrial ROS in neurodegenerative diseases. Dr. Adam Orr explained, "Pathological ties between ROS and these disorders have been established, leading to efforts to combat them using antioxidants." However, most clinical studies with antioxidants have failed, possibly due to their inability to block ROS at their source selectively.
A Unique Solution: S3QELs
Dr. Adam Orr, during his postdoctoral fellowship, developed a novel drug-discovery platform. This platform identified small molecules called S3QELs that could precisely suppress ROS production from specific sites in mitochondria without disrupting other vital functions.
The researchers targeted Complex III, a site for oxidative metabolism that tends to release ROS from mitochondria into the rest of the cell. Here's where it gets controversial: the ROS didn't originate from the neurons' mitochondria but from astrocytes cultured with the neurons. When the researchers added S3QELs, they observed significant neuronal protection, suggesting that ROS from Complex III contributed to neuronal pathology.
Daniel Barnett, a graduate student in the Orr laboratory and lead author, further investigated this phenomenon. He found that exposing astrocytes to disease-related factors, such as neuroinflammatory molecules or proteins associated with dementia, increased their mitochondrial ROS production. S3QELs effectively suppressed this increase, highlighting the specificity of their action.
The Impact of ROS on the Brain
Barnett's research revealed that ROS oxidized specific immune and metabolic proteins linked to neurological diseases. This oxidation influenced the activity of thousands of genes, particularly those involved in brain inflammation and associated with dementia. The degree of specificity was unexpected and intriguing, suggesting a nuanced process where specific triggers induce ROS from specific mitochondrial sites to target precise cellular components.
A New Therapeutic Approach
When the researchers administered their S3QEL ROS inhibitor to a mouse model of frontotemporal dementia, they observed reduced astrocyte activation, blunted neuroinflammatory genes, and a decrease in tau modification seen in dementia patients. Even when the treatment was initiated after the disease process had started, it still showed positive results. Prolonged treatment with S3QEL extended the lifespan of the mice without any obvious side effects.
The team, in collaboration with Dr. Subhash Sinha, aims to develop these compounds into a new therapeutic for neurodegenerative disorders. Simultaneously, they will continue exploring how disease-linked factors influence ROS production in the brain and investigate the influence of genes associated with an increased or decreased risk of these diseases on ROS generation from specific mitochondrial sites.
Dr. Adam Orr concluded, "This study has truly shifted our understanding of free radicals, opening up numerous new avenues for investigation."
Source: Barnett, D., et al. (2025). Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology. Nature Metabolism. doi.org/10.1038/s42255-025-01390-y
