Targeting PGC-1α axis Rescues Aberrant Development from Thyroid Hormone Defect in Brain Organoids

: Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.