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

Yicheng Wang, Pengfei Song, Heqing Zhou, Pengwei Wang, Yan Li, Zhiyong Shao, Lu Wang, Yan You (), Zuhai Lei (), Jinhua Yu () and Cong Li ()
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Yicheng Wang: Fudan University
Pengfei Song: Fudan University
Heqing Zhou: Fudan University
Pengwei Wang: Fudan University
Yan Li: Fudan University
Zhiyong Shao: Fudan University
Lu Wang: Fudan University
Yan You: Fudan University
Zuhai Lei: Yunnan University
Jinhua Yu: Fudan University
Cong Li: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60315-1

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