Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy

作者：Ang Li, Sen Huang, Shuqin Cao, Jinyi Lin, Linping Zhao, Feng Yu, Miaodan Huang, Lei Yang, Jiaqi Xin, Jing Wen, Lingli Yan, Ke Zhang, Maoyuan Jiang, Weidong Le, Peng Li, Yong Liu, Dajiang Qin, Jiahong Lu, Guang Xiu Lu, Han‐Ming Shen, Xiaoli Yao, Evandro Fei Fang, Huanxing Su · 发表于：EMBO Molecular Medicine · 年份：2025 · DOI：10.1038/s44321-025-00323-2 · 被引用次数：13 · 研究领域：Amyotrophic Lateral Sclerosis Research、Parkinson's Disease Mechanisms and Treatments、Autophagy in Disease and Therapy

Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.