Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos

Beatriz Villarejo-Zori; Juan Zapata-Muñoz; Elena Sierra-Filardi; Ignacio Ramírez-Pardo; Lambert Montava-Garriga; Ian G. Ganley; Patricia Boya

doi:10.1038/s41419-025-07686-x

Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos

Beatriz Villarejo-Zori (Lead / Corresponding author)
, Juan Zapata-Muñoz
, Elena Sierra-Filardi
, Ignacio Ramírez-Pardo
, Lambert Montava-Garriga
, Ian G. Ganley
, Patricia Boya (Lead / Corresponding author)

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Abstract

Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. (Figure presented.)

Original language	English
Article number	402
Journal	Cell Death and Disease
Volume	16
Issue number	1
Early online date	19 May 2025
DOIs	https://doi.org/10.1038/s41419-025-07686-x
Publication status	Published - 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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Cite this

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title = "Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos",

abstract = "Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. (Figure presented.)",

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doi = "10.1038/s41419-025-07686-x",

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AU - Villarejo-Zori, Beatriz

AU - Zapata-Muñoz, Juan

AU - Sierra-Filardi, Elena

AU - Ramírez-Pardo, Ignacio

AU - Montava-Garriga, Lambert

AU - Ganley, Ian G.

AU - Boya, Patricia

PY - 2025

Y1 - 2025

N2 - Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. (Figure presented.)

AB - Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. (Figure presented.)

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Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos

Abstract

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