2. Academic Validation
  3. Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy

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

  • EMBO Mol Med. 2025 Oct 15. doi: 10.1038/s44321-025-00323-2.
Ang Li # 1,  Sen Huang # 2,  Shu-Qin Cao # 3,  Jinyi Lin 4,  Linping Zhao 5,  Feng Yu 1,  Miaodan Huang 1,  Lele Yang 1,  Jiaqi Xin 1,  Jing Wen 1,  Lingli Yan 1,  Ke Zhang 1,  Maoyuan Jiang 1,  Weidong Le 6,  Peng Li 1,  Yong U Liu 7,  Dajiang Qin 5,  Jiahong Lu 1,  Guang Lu 4,  Hanming Shen 8,  Xiaoli Yao 9,  Evandro F Fang 10 11,  Huanxing Su 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
  • 3 Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, 1478, Norway.
  • 4 Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 6 Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 7 Laboratory for Neuroimmunology in Health and Diseases, Centre for Medical Research on Innovation and Translation, Institute of Clinical Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
  • 8 Faculty of Health Sciences, University of Macau, Macau, China.
  • 9 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China. yaoxiaol@mail.sysu.edu.cn.
  • 10 Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, 1478, Norway. e.f.fang@medisin.uio.no.
  • 11 The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway. e.f.fang@medisin.uio.no.
  • 12 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. huanxingsu@um.edu.mo.
  • # Contributed equally.
PMID: 41094045 DOI: 10.1038/s44321-025-00323-2
Abstract

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.

Keywords

Amyotrophic Lateral Sclerosis; Drug Screening; Isoginkgetin; Mitophagy; PINK1-Parkin.

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