Thyroid hormone (T3) plays a critical role during early brain and overall central nervous system (CNS) development, and it acts as a major regulator of CNS metabolism and mitochondrial activity.Mutations in the T3 specific receptor monocarboxylate transporter 8 (MCT8) lead to hypothyroidism condition as tough in the Allan Herndon Dudley Syndrome (AHDS), which is characterized by neurodevelopmental defects.We set up a brain organoid model resembling AHDS pathological scenario to study the neurodevelopmental defects and to screen new metabolic target to restore neuronal maturation.AHDS organoids were characterized by an immature profile with delayed maturation and low spontaneous functional activity compared to control brain organoids. Notably, in AHDS organoids, astrocytes were the most represented cellular population at the expenses of the neuronal one, suggesting a reduced neuronal commitment of the differentiating neural stem cells. Transcriptomic analysis confirmed the immature profile of AHDS organoids and revealed the impairment of fatty acid metabolism and mitochondrial dynamics, and the overexpression of NOTCH signaling pathway. Pharmacological modulation of mitochondrial metabolism was able to reduce stemness and content of glial cells, and to partially restore the correct neural development in AHDS brain organoids.Overall, this data indicated that targeting mitochondrial metabolism may be an efficient strategy to restore neurodevelopment defects due to T3 deficiency.