Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy
Summary
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. © 2025. The Author(s).
| Authors | Li A, Huang S, Cao SQ, Lin J, Zhao L, Yu F, Huang M, Yang L, Xin J, Wen J, Yan L, Zhang K, Jiang M, Le W, Li P, Liu YU, Qin D, Lu J, Lu G, Shen H, Yao X, Fang EF, Su H |
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| Journal | EMBO molecular medicine |
| Publication Date | 2025 Nov;17(11):3139-3173 |
| PubMed | 41094045 |
| PubMed Central | PMC12603167 |
| DOI | 10.1038/s44321-025-00323-2 |