title: Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress.
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 H2O2and 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.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Mateus P
authors.identifier: 0000-0003-1349-6378
authors.initials: MP
authors.lastname: Mori
authors.affiliation: Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Rute A P
authors.identifier: 0000-0003-1795-9819
authors.initials: RA
authors.lastname: Costa
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Daniela T
authors.identifier: 0000-0002-1024-3108
authors.initials: DT
authors.lastname: Soltys
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Thiago de S
authors.initials: TS
authors.lastname: Freire
authors.affiliation: Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Franco A
authors.identifier: 0000-0002-4132-2271
authors.initials: FA
authors.lastname: Rossato
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Ignácio
authors.initials: I
authors.lastname: Amigo
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Aníbal E
authors.initials: AE
authors.lastname: Vercesi
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, Brazil. nadja@iq.usp.br.
authors.forename: Nadja C
authors.initials: NC
authors.lastname: de Souza-Pinto
mesh_terms: D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism*; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D017384:Sequence Deletion; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C478189:respiratory complex II; C086984:XPC protein, human; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I