Abstract
Photoreceptors (PRs) are specialized light-sensitive cells responsible for vision, and their death is the primary cause of retinal degeneration and vision loss. Recent studies using cells such as HeLa and PC12 have demonstrated cellular recovery even from late stages of apoptosis. Here, we demonstrate for the first time that PR cells can recover from features of apoptosis following exposure to apoptotic stressors. Upon apoptotic stimuli (staurosporine or hypoxia), 661 W cells, a murine cone PR cell line, exhibited morphological and functional features of apoptosis, such as rounding and blebbing, caspase-3 activation, PARP cleavage, and phosphatidylserine externalization. These processes were reversed upon the alleviation of stress. We also observed that mitochondrial function is central to apoptotic recovery of photoreceptor cells, as evidenced by the restoration of intracellular ATP levels and reduction in mitochondrial reactive oxygen species (mROS). Mitophagy was demonstrated to play a crucial role in cell survival, with increased protein and mRNA expression of mitophagy markers during recovery from apoptosis. Furthermore, the modulation of mitophagy confirmed its protective role in the recovery phase, as its induction with MF-094 reduced apoptosis while its inhibition with Mdivi-1 exacerbated cell death. In vivo, we demonstrate the recovery of PRs from apoptosis using an experimental model of transient retinal detachment. Altogether, the findings of this study indicate that PR cells can recover from entry into the apoptotic cascade, and that mitophagy is essential for apoptotic recovery in these cells.
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All data generated and analyzed in this study are presented in this published article. Primary data may be made available from the corresponding author upon reasonable request.
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Acknowledgements
This work utilized the University of Michigan Vision Research Core, which is funded by P30 EY007003 from the National Eye Institute.
Funding
D.N.Z. was supported by NIH R01EY020823. D.N.Z. is also a 2025 Alcon Research Institute (“ARI”) Senior Investigator Grant Recipient, which supported this work. B.M.S. was supported by Training Grant T32AR07080 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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D.N.Z. study conceptualization, project supervision, and manuscript preparation. B.K., B.M.S. and J.Y. experimental design, experiments, data analysis and manuscript preparation. M.Y. and L.J. transient detachment experiments and data analysis. S.I.L. microscopy and image analysis. J.S. experiments and data analysis, A.K. experimental design and data analysis. S.S. flow cytometry experimental design, experiments, data analysis. All authors read and approved the manuscript.
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D.N.Z. is an employee of the University of Michigan and ONL Therapeutics. D.N.Z. also holds patents through the University of Michigan that are licensed to ONL Therapeutics. A.K. is an employee of ONL Therapeutics. All other authors declare no conflict of interest.
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Animal experiments were performed following the protocols approved by the Institutional Animal Care & Use Committee (IACUC) at the University of Michigan and in compliance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Visual Research.
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Kaur, B., Miglioranza Scavuzzi, B., Yao, J. et al. Recovery from apoptosis in photoreceptor cells: A role for mitophagy. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08436-3
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DOI: https://doi.org/10.1038/s41419-026-08436-3


