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

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-10-15
DOI
https://doi.org/10.1038/s44321-025-00323-2
Citations
4
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
5.56
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article

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

Dajiang Qin, Linping Zhao, Weidong Le, Jinyi Lin et al.
4 citations
EMBO Molecular Medicine
Amyotrophic Lateral Sclerosis Research
5.56
article

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

Dajiang Qin, Linping Zhao, Weidong Le, Jinyi Lin, Maoyuan Jiang, Han‐Ming Shen, Sen Huang, Huanxing Su, Feng Yu, Jing Wen, Guang Xiu Lu, Evandro Fei Fang, Miaodan Huang, Jiahong Lu, Xiaoli Yao, Yong Liu, Ang Li, Peng Li, Lei Yang, Ke Zhang, Jiaqi Xin, Shuqin Cao, Lingli Yan
article en
4 citations

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.

EMBO Molecular MedicineVol. 17(11)
Sun Yat-sen University (CN), University of Oslo (NO), Dalian Medical University (CN), University of Macau (MO), Akershus University Hospital (NO), Second Affiliated Hospital of Guangzhou Medical University (CN), Key Laboratory of Guangdong Province (CN), NORCE Research AS (NO), The First Affiliated Hospital, Sun Yat-sen University (CN), First Affiliated Hospital of Dalian Medical University (CN), Guangzhou Medical University (CN)
Openalex Percentile: Top 4%
Amyotrophic Lateral Sclerosis Research
5.56
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