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Xeroderma pigmentosum group A protein modulates mitophagy through regulation of mitochondrial‐associated proteins
Author(s) -
Fang Evandro Fei,
ScheibyeKnudsen Morten,
Croteau Deborah L.,
Bohr Vilhelm A.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb468
Subject(s) - xeroderma pigmentosum , mitophagy , mitochondrion , biology , nucleotide excision repair , microbiology and biotechnology , cancer research , autophagy , genetics , apoptosis , dna repair , gene
The Xeroderma pigmentosum group A (XPA) protein plays critical roles in nucleotide excision repair pathway (NER), and patients with XPA deficiency exhibit sun sensitivity, high skin cancer predisposition, and many have progressive neurological disorders. Based on a clinical database that we have established (Scheibye‐Knudsen et al, submitted) we speculated that there might be mitochondrial dysfunction in individuals with XPA. We therefore investigated mitochondrial function in XPA deficient cells, in primary fibroblasts from patients with XPA and compared these to controls and to cell lines complemented with the normal XPA gene. Microarray analysis indicated increased mitochondrial metabolism in XPA deficient cells, and flow cytometry results showed an increase in mitochondrial content. Cellular and mitochondrial reactive oxygen species (ROS) and the mitochondrial membrane potential (MMP) were increased in XPA cells. These cells also had increased numbers of damaged mitochondria and a deficiency in mitophagy after mitochondrial stress. These findings uncover a novel mitochondrial defect in XPA which could be an important factor in the clinical phenotype. We discuss the dysregulation of important mitochondrial proteins in XPA and propose a mechanism.