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Fibroblasts and hiPS ‐Derived Astrocytes From CoPAN Patients Showed Different Levels of Iron Overload Correlated With Senescent Phenotype
Author(s) -
Cozzi Anna,
Santambrogio Paolo,
Moro Andrea Stefano,
Pelagatti Alessio,
Rubio Alicia,
Balestrucci Chiara,
Di Meo Ivano,
Tiranti Valeria,
Levi Sonia
Publication year - 2025
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.70017
Subject(s) - neurodegeneration , biology , senescence , phenotype , microbiology and biotechnology , mitochondrion , cytosol , biochemistry , gene , pathology , enzyme , medicine , disease
ABSTRACT COASY protein‐associated neurodegeneration (CoPAN) is a rare autosomal recessive disorder within the Neurodegeneration with Brain Iron Accumulation spectrum, resulting from mutations in COASY . This gene encodes the bifunctional enzyme essential for the final steps of coenzyme A biosynthesis. To elucidate the pathophysiology and iron dyshomeostasis underlying CoPAN, we analyzed fibroblasts and human induced pluripotent stem (hiPS)‐derived astrocytes from two patients carrying distinct COASY mutations. Our findings reveal that CoPAN fibroblasts display altered iron homeostasis, characterized by iron aggregates, elevated cytosolic labile iron pool, and impaired tubulin acetylation. Patients hiPS‐derived astrocytes showed mitochondrial morphological abnormalities and compromised vesicular trafficking. Notably, both cell types demonstrated evidence of ferroptosis, but the astrocytes exhibited more pronounced iron accumulation and lipid peroxidation. These results demonstrate that astrocytes may more accurately recapitulate the pathological phenotype of CoPAN compared to fibroblasts. Interestingly, astrocytes exhibited different levels of iron accumulation concomitant with cellular senescence, indicating a possible role of iron‐induced cellular senescence. This finding suggests that the accumulation of cytosolic iron, possibly caused by mitochondrial dysfunction, actively promotes senescence. Our data emphasize the potential therapeutic efficacy of drugs that enhance mitochondrial functionality to attenuate the effects of CoPAN.