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Updated: Nov 4, 2025
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia
Noemí Esteras1, Olga Kopach2, Marta Maiolino3
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Introduction:
The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation.
Methods:
Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures.
Results:
Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation.
Discussion:
These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.
Insights
Frontotemporal dementia (FTD) involves tau protein aggregation. This study shows mitochondrial reactive oxygen species (ROS) disrupt neuronal function in FTD, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Frontotemporal dementia (FTD) is a common early-onset dementia.
- FTD is characterized by the aggregation of tau protein.
- The 10+16 MAPT mutation is linked to FTD and tau pathology.
Purpose of the Study:
- To investigate the mechanism of tau-induced neuronal dysfunction in FTD.
- To explore the role of the 10+16 MAPT mutation in FTD pathogenesis.
- To identify potential therapeutic strategies for FTD.
Main Methods:
- Utilized induced pluripotent stem cell-derived neurons with the 10+16 MAPT mutation.
- Employed live imaging, electrophysiology, and redox proteomics.
- Developed a model for studying tau spreading in primary neuronal cultures.
Main Results:
- Mitochondrial reactive oxygen species (ROS) overproduction in 10+16 neurons dysregulates glutamate receptor trafficking.
- Increased surface expression of AMPA and NMDA receptors leads to excitotoxicity.
- Mitochondrial antioxidants reversed pathological changes and prevented neuronal death.
- Extracellular tau induced similar pathology in healthy neurons, suggesting disease propagation.
Conclusions:
- Mitochondrial ROS play a critical role in modulating glutamatergic signaling in FTD.
- Targeting mitochondrial ROS presents a novel therapeutic avenue for FTD.
- Tau pathology can propagate to healthy neurons, contributing to disease progression.
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