BIN Mentee Spotlight: Savannah Cooper

Neurodegenerative Cognitive Impairment in Mice Improved with Altered Mitochondria Activity

Mitochondria, or colloquially known as the “powerhouse of the cell,” is an essential organelle that is involved with several important physiological functions. Its product, adenosine triphosphate (ATP), restores and powers the propagation of action potentials, which triggers the release of neurotransmitters and intracellular ions throughout neuronal and muscular synapses. Without them, neurons lack the energy to carry out signal transmission and information processing. Conversely, mitochondrial dysfunction has been found to be an important factor in several neurological (e.g. autism) and neurodegenerative disorders or tauopathies, such as Alzheimer’s and Parkinson’s. However, for researchers, establishing mitochondrial dysfunction as a precursor or a product  in these brain-related disorders has been difficult.

In a recent study, published by Nature Neuroscience, researchers from INSERM, the University of Bordeaux, and the Université de Moncton collaborated to develop a  chemogenetic construct, DREADD, that exclusively activates mitochondrial signaling and activity. The researchers  hypothesized that if mitochondrial dysfunction is the cause of cognitive symptoms seen in neurological disorders, then increasing mitochondrial activity will improve these symptoms.

Researchers based their understanding of the role G proteins (GPCRs) have in cellular functions and that various GPCRS have been found to be present in mitochondrial membranes. Thus, they reasoned in generating an artificial receptor, MitoDREADD-Gₛ, using mitochondrial leading sequences, that was inserted into the outer mitochondrial membrane in mice hippocampi, a region involved in memory. The direct activation of the receptor, upon the use of the agonist Clozapine-N-Oxide (CNO, stimulated mitochondrial activity; specifically, the rate of oxygen consumption, cAMP generation, and the phosphorylation of protein kinase A (PKA) increased. Furthermore, mice models expressing the P301S mutant tau protein, with symptoms of Frontotemporal Dementia (FTD) and Alzheimer's disease, were found to have memory impairment in novel object recognition tests. Upon MitoDREADD-Gₛ activation, improvement in those tasks were seen in the P301S mice. Thus, MitoDREADD-Gₛ was found to be a powerful tool in improving cognitive performances and mitochondrial activity in mice who present with the cognitive and behavioral symptoms associated with neurodegenerative disorders.

Pagano Zottola, A.C., Martín-Jiménez, R., Lavanco, G., et al.’s work with a chemogenetic tool contributes to the difficult question of whether mitochondrial alterations play a consequential role in neurological and neurodegenerative diseases. The researchers established a causal link between mitochondrial dysfunction and pathophysiological processes of diseases and disorders. It suggests that the impaired mitochondrial activity may be the root cause of neuronal degeneration. Nevertheless, this research could serve as a foundation for future studies exploring therapeutic interventions and concepts that aim to improve disorders and diseases associated with altered mitochondrial activity.

Reference:

Pagano Zottola, A.C., Martín-Jiménez, R., Lavanco, G. et al. Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice. Nat Neurosci 28, 1844–1857 (2025). https://doi.org/10.1038/s41593-025-02032-y

Savannah Cooper holds a Bachelor of Science in Neuroscience from Mercer University, with a strong passion for research in neurotoxicity of addiction and therapeutics targeting neurodegenerative diseases and disorders. During a brief research assistant position, she conducted research on the foraging and daily behavior of gerbils. Currently, she is applying to a master’s program with the intention of matriculating in Fall 2026. Her ultimate goal is to join a lab that investigates the genetic or environmental precursors to addiction and neurodegeneration. In the future, she envisions herself as a researcher in translational research that contributes to the development meaningful treatments for individuals with addiction or neurological diseases in real-world settings.