Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN

Autor: Alejandra Suárez-Carrillo, Mónica Álvarez-Córdoba, Ana Romero-González, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, Rocío Piñero-Pérez, Diana Reche-López, David Gómez-Fernández, José Manuel Romero-Domínguez, Manuel Munuera-Cabeza, Antonio Díaz, Susana González-Granero, José Manuel García-Verdugo, José A. Sánchez-Alcázar
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 24, Iss 19, p 14576 (2023)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms241914576
Popis: Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.
Databáze: Directory of Open Access Journals
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