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

Autor(es)

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.

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 7, MAR 13 2017.
• Citações Web of Science: 6

Resumo

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)

• Processo FAPESP: 12/11889-6 - Estudo das atividades de reparo de DNA por excisão de bases em cérebros de indivíduos acometidos pela Doença de Alzheimer
• Beneficiário: Daniela Tathiana Soltys
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 08/57952-5 - Instituto Nacional de Obesidade e Diabetes
• Beneficiário: Mario Jose Abdalla Saad
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/51906-1 - Bioenergética, transporte iônico, balanço redox e metabolismo de DNA em mitocôndrias
• Beneficiário: Alicia Juliana Kowaltowski
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 08/57721-3 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/59786-0 - Metabolismo energético, homeostase intracelular de CA2+ e estresse oxidativo mitocondrial na morte celular
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs