Targeting PGC-1α axis rescues aberrant development from thyroid hormone defect in brain organoids
Emanuela Bottani1, Francesca Ciarpella1, Benedetta Lucidi1
1Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy.
Pharmacological Research
|December 19, 2025
Summary
Thyroid hormone (T3) deficiency impairs brain development by disrupting mitochondrial function. Stimulating the PGC-1α pathway with specific compounds offers a potential treatment for these severe neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Mitochondrial Biology
Background:
- Thyroid hormone (T3) is crucial for central nervous system development.
- T3 deficiency causes severe neurodevelopmental pathologies like intellectual disability and motor dysfunction.
- The precise mechanisms by which T3 supports neurodevelopment are not fully understood.
Purpose of the Study:
- To elucidate the role of T3 in neuronal development and mitochondrial function.
- To identify key molecular mediators of T3's effects on the developing brain.
- To explore therapeutic strategies for T3 deficiency-related neurodevelopmental disorders.
Main Methods:
- Utilized murine dorsal forebrain organoids to model T3 deficiency.
- Assessed mitochondrial β-oxidation and oxidative phosphorylation (OXPHOS) biogenesis.
- Investigated the role of the transcriptional coactivator PGC-1α.
- Employed pharmacological interventions targeting β-oxidation and the PGC-1α axis.
Main Results:
- T3 deficiency severely impaired neuronal maturation, increased astrogliosis, and reduced neuronal activity in brain organoids.
- T3 activates mitochondrial β-oxidation and OXPHOS biogenesis, essential for neuronal development.
- PGC-1α acts as a central mediator of T3's effects; its augmentation rescued development in T3-deprived conditions.
- Pharmacological activation of the PGC-1α axis (using Nicotinamide Riboside or Bezafibrate) rescued mitochondrial function and corrected neurodevelopmental defects despite T3 deficiency.
Conclusions:
- T3 is essential for activating mitochondrial bioenergetics, specifically β-oxidation and OXPHOS, to support neurodevelopment.
- The PGC-1α pathway is a critical mediator of T3's neurodevelopmental functions.
- Targeting the PGC-1α axis presents a promising therapeutic strategy for neurodevelopmental disorders caused by thyroid hormone deficiency.
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