miR-125b Mediates Tau-induced Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease
Laura De Plano1, Alessandra Saitta1,2, Aurelio Minuti3
1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy.
Abstract:
MicroRNA (miRNA) dysregulation contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), but the role of specific miRNAs in tau-mediated toxicity remains unclear. Here, we investigated the contribution of hsa-miR-125b to tau-induced cellular dysfunction using a stable neuronal cell line overexpressing mutant tau (P301L). We found that hsa-miR-125b levels were significantly elevated in tau-expressing cells compared to controls. Using bioinformatic tools, we identified a strong enrichment of predicted hsa-miR-125b targets involved in mitochondrial function. We validated several of these targets by RT-qPCR and confirmed the downregulation of mitochondrial-related transcripts, including genes encoding components of complexes I, IV, and V of the electron transport chain. To assess functional consequences, we performed Seahorse metabolic flux analysis and observed impaired mitochondrial respiration in tau-overexpressing cells, including reduced basal respiration, ATP production, and spare respiratory capacity. Our findings demonstrate that hsa-miR-125b contributes to tau-induced mitochondrial dysfunction by repressing transcripts essential for mitochondrial homeostasis. We propose that hsa-miR-125b acts as a mechanistic link between tau pathology and metabolic impairment in AD and may represent a promising target for therapeutic intervention.
Insights
MicroRNA-125b levels increase in Alzheimer's disease models, impairing mitochondrial function by targeting key respiratory genes. This suggests microRNA-125b links tau pathology to metabolic deficits, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- MicroRNA (miRNA) dysregulation is implicated in neurodegenerative diseases like Alzheimer's disease (AD).
- The specific role of miRNAs in tau-mediated neurotoxicity, a hallmark of AD, requires further elucidation.
- Understanding miRNA involvement in tau pathology is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the contribution of hsa-miR-125b to cellular dysfunction caused by mutant tau (P301L) expression.
- To identify and validate targets of hsa-miR-125b involved in mitochondrial function.
- To assess the functional impact of hsa-miR-125b on mitochondrial respiration in a cellular model of tauopathy.
Main Methods:
- Utilized a stable neuronal cell line overexpressing mutant tau (P301L).
- Quantified hsa-miR-125b levels and validated predicted miRNA targets using RT-qPCR.
- Assessed mitochondrial function via Seahorse metabolic flux analysis.
Main Results:
- hsa-miR-125b levels were significantly elevated in tau-expressing cells.
- Bioinformatic analysis revealed enrichment of mitochondrial function-related targets for hsa-miR-125b.
- Downregulation of mitochondrial electron transport chain complex transcripts (I, IV, V) and impaired mitochondrial respiration (basal respiration, ATP production, spare capacity) were observed.
Conclusions:
- hsa-miR-125b exacerbates tau-induced mitochondrial dysfunction by downregulating essential mitochondrial homeostasis transcripts.
- hsa-miR-125b serves as a mechanistic link between tau pathology and metabolic impairment in Alzheimer's disease.
- hsa-miR-125b represents a potential therapeutic target for mitigating tau-mediated neurotoxicity and metabolic deficits in AD.
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