Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress

• Published in: Scientific reports 2017-03, Vol.7 (1), p.155-155, Article 155
• Main Authors: Mori, Mateus P., Costa, Rute A. P., Soltys, Daniela T., Freire, Thiago de S., Rossato, Franco A., Amigo, Ignácio, Kowaltowski, Alicia J., Vercesi, Aníbal E., de Souza-Pinto, Nadja C.
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/51; 14/1; 14/34; 38/39; 38/77; 631/337/1427/1430; 631/80/642/333/1465; Cell Line; DNA, Mitochondrial - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electron Transport Complex I - metabolism; Electron Transport Complex II - metabolism; Gene Expression Regulation; Glutathione Peroxidase - metabolism; Humanities and Social Sciences; Humans; Hydrogen Peroxide - metabolism; Mitochondria - genetics; Mitochondria - metabolism; multidisciplinary; Oxidative Stress; Science; Science (multidisciplinary); Sequence Deletion; Xeroderma Pigmentosum - genetics; Xeroderma Pigmentosum - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00130-x

Genomic instability drives tumorigenesis and DNA repair defects are associated with elevated cancer. Metabolic alterations are also observed during tumorigenesis, although a causal relationship between these has not been clearly established. Xeroderma pigmentosum (XP) is a DNA repair disease characterized by early cancer. Cells with reduced expression of the XPC protein display a metabolic shift from OXPHOS to glycolysis, which was linked to accumulation of nuclear DNA damage and oxidants generation via NOX-1. Using XP-C cells, we show that mitochondrial respiratory complex I (CI) is impaired in the absence of XPC, while complex II (CII) is upregulated in XP-C cells. The CI/CII metabolic shift was dependent on XPC, as XPC complementation reverted the phenotype. We demonstrate that mitochondria are the primary source of H 2 O 2 and glutathione peroxidase activity is compromised. Moreover, mtDNA is irreversibly damaged and accumulates deletions. XP-C cells were more sensitive to the mitochondrial inhibitor antimycin A, an effect also prevented in XPC-corrected cells. Our results show that XPC deficiency leads to alterations in mitochondrial redox balance with a CI/CII shift as a possible adaptation to lower CI activity, but at the cost of sensitizing XP-C cells to mitochondrial oxidative stress.