P2 Receptor Antagonists Rescue Defective Heme Content in an In Vitro SLC25A38-Associated Congenital Sideroblastic Anemia Cell Model
Mutations in the SLC25A38 gene are responsible for the second most common form of congenital sideroblastic anemia (CSA), a severe condition for which no effective treatment exists. We developed and characterized a K562 erythroleukemia cell line with markedly reduced expression of the SLC25A38 protein (A38-low cells). This model successfully recapitulated the main features of CSA, including reduced heme content and mitochondrial respiration, increase in mitochondrial iron, ROS levels and sensitivity to oxidative stress. Notably, our study uncovered a new role for extracellular pyridoxal 5'-phosphate (PLP) and other P2 receptor antagonists in rescuing the altered parameters of A38-low cells (for example, the heme content of the A38-low cells was increased from about 50% to about 80% by the P2 receptor antagonists treatment compared with the value of the controls). These findings suggest that targeting P2 receptors could represent a promising therapeutic approach for SLC25A38-associated CSA.
Authors
- Eleonora Paradies
- Silvia De Santis (ORCID: https://orcid.org/0000-0003-1822-8081)
- Achille Iolascon (ORCID: https://orcid.org/0000-0002-9558-0356)
- Arianna Ferrucci
- Antonio J. Palazzo (ORCID: https://orcid.org/0000-0003-0961-6832)
- Immacolata Andolfo (ORCID: https://orcid.org/0000-0003-0493-812X)
- Clelia Tiziana Storlazzi (ORCID: https://orcid.org/0000-0002-1696-0028)
- Antonella Santoro (ORCID: https://orcid.org/0000-0002-6193-2050)
- Yong Woong Jun (ORCID: https://orcid.org/0000-0001-9359-1265)
- Giuseppe Fiermonte (ORCID: https://orcid.org/0000-0002-6764-9395)
- Luigi Palmieri (ORCID: https://orcid.org/0000-0002-6503-2922)
- Angelo Vozza (ORCID: https://orcid.org/0000-0002-2433-465X)
- Eric T. Kool (ORCID: https://orcid.org/0000-0002-7310-2935)
- Gennaro Agrimi (ORCID: https://orcid.org/0000-0002-5219-4412)
- C Marobbio (ORCID: https://orcid.org/0000-0002-2516-0321)
- Roberta Russo (ORCID: https://orcid.org/0000-0002-3624-7721)
- Ferdinando Palmieri
Institutions
- Korea Advanced Institute of Science and Technology (KR)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IT)
- University of Bari Aldo Moro (IT)
- University of Naples Federico II (IT)
- Stanford University (US)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2024-12-12
- DOI
- https://doi.org/10.3390/ijms252413314
- Citations
- 2
- Primary Topic
- Neonatal Health and Biochemistry
- Type
- article
- Field-Weighted Citation Impact
- 2.22
Funders
- National Cancer Institute