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

Author(s)

Mori, Mateus P. ; Costa, Rute A. P. ; Soltys, Daniela T. ; Freire, Thiago de S. ; Rossato, Franco A. ; Amigo, Ignacio ; Kowaltowski, Alicia J. ; Vercesi, Anbal E. ; de Souza-Pinto, Nadja C.

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, MAR 13 2017.
• Web of Science Citations: 6

Abstract

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 H2O2 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. (AU)

• FAPESP's process: 12/11889-6 - Status of DNA base excision repair in brain from individuals with Alzheimer's Disease
• Grantee: Daniela Tathiana Soltys
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 08/57952-5 - National Institute of Obesity and Diabetes
• Grantee: Mario Jose Abdalla Saad
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 08/57721-3 - Redoxome
• Grantee: Ohara Augusto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 06/59786-0 - Energetic metabolism, intracellular homeostasis of CA2+ and mitochondrial oxidative stress in cell death
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC