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<p>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 (<i>n</i> = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from <i>Ginkgo biloba</i>, 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 <i>C. elegans</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Ang Li,
  • Sen Huang,
  • Shu-qin Cao,
  • Jinyi Lin,
  • Linping Zhao,
  • Feng Yu,
  • Miaodan Huang,
  • Lele Yang,
  • Jiaqi Xin,
  • Jing Wen,
  • Lingli Yan,
  • Ke Zhang,
  • Maoyuan Jiang,
  • Weidong Le,
  • Peng Li,
  • Yong U Liu,
  • Dajiang Qin,
  • Jiahong Lu,
  • Guang Lu,
  • Hanming Shen,
  • Xiaoli Yao,
  • Evandro F Fang,
  • Huanxing Su

摘要

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.