01888nas a2200301   4500000000100000000000100001008004100002260000900043653000900052653002300061653000900084653002700093653001100120100001500131700002000146700001200166700003000178700002500208700002400233700002400257700002400281245010500305856006700410300001200477490000700489520107600496022001401572       2024                            d  c202410aPOLG10acortical organoids10aiPSC10amitochondrial function10aneuron1 aAnbin Chen1 aTsering Yangzom1 aYu Hong1 aBjørn Christian Lundberg1 aGareth John Sullivan1 aCharalampos Tzoulis1 aLaurence A. Bindoff1 aKristina Xiao Liang00aHallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202307136  a23071360 v113 aIn this research, a 3D brain organoid model is developed to study POLG-related encephalopathy, a mitochondrial disease stemming from POLG mutations. Induced pluripotent stem cells (iPSCs) derived from patients with these mutations is utilized to generate cortical organoids, which exhibited typical features of the diseases with POLG mutations, such as altered morphology, neuronal loss, and mitochondiral DNA (mtDNA) depletion. Significant dysregulation is also identified in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK-STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory dopamine-glutamate (DA GLU) neurons. This novel model effectively mirrors both the molecular and pathological attributes of diseases with POLG mutations, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG-related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.  a2198-3844