2. Academic Validation
  3. An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates

An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates

  • Nat Commun. 2025 Jun 4;16(1):5179. doi: 10.1038/s41467-025-60315-1.
Yicheng Wang # 1,  Pengfei Song # 2,  Heqing Zhou # 1,  Pengwei Wang 1,  Yan Li 3,  Zhiyong Shao 4 5,  Lu Wang 1,  Yan You 6,  Zuhai Lei 7,  Jinhua Yu 8,  Cong Li 9 10 11
Affiliations

Affiliations

  • 1 School of Pharmacy; MOE Key Laboratory of Smart Drug Delivery; MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases; Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 College of Biomedical Engineering, Fudan University, Shanghai, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
  • 4 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 5 Institutes of Brain Science, Fudan University, Shanghai, China.
  • 6 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China. yyou@fudan.edu.cn.
  • 7 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Pharmacy, Yunnan University, Kunming, China. lei_zuhai@fudan.edu.cn.
  • 8 College of Biomedical Engineering, Fudan University, Shanghai, China. jhyu@fudan.edu.cn.
  • 9 School of Pharmacy; MOE Key Laboratory of Smart Drug Delivery; MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases; Zhongshan Hospital, Fudan University, Shanghai, China. congli@fudan.edu.cn.
  • 10 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. congli@fudan.edu.cn.
  • 11 The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Shenzhen, China. congli@fudan.edu.cn.
  • # Contributed equally.
PMID: 40467562 DOI: 10.1038/s41467-025-60315-1
Abstract

Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of Mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening Mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential Mitophagy modulator, Y040-7904, which enhances Mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces Amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire Mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of Mitophagy inducers for neurodegenerative diseases.

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