Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient‐Derived Brain Organoids
Year: 2025
Type: article
Abstract: Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin-induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox-related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG-related disorders.
Source: Advanced Science
Authors: Zhuoyuan Zhang, Tsering Yangzom, Ning Lu, Shenglong Deng, Xianglu Xiao, Guang Yang, Kristina Xiao Liang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Funders: Nvidia, UK Research and Innovation, Royal Society, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Universitetet i Bergen, Horizon 2020 Framework Programme, Medical Research Council, NIHR Imperial Biomedical Research Centre
Awards: G1251990094, G1285418384, G2597775472, Fully Automatic Segmentation and Assessment of Atrial Scars for Atrial Fibrillation Patients
Using LGE MRI, G6756521213, G7986630670, Synergistic Inverse Problems Omni-Solver for Expeditious High Quality Multimodal Cardiovascular MRI via Deep Compressive Sensing and Data Coalescing, Novel Data-Driven Models for robust and generalisable ultra-low-dose PET image reconstruction and high-quality CT-free PET image synthesis
OpenAlex ID: W4417110256