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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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.
Total Authors: 9
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 type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
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 type: Research Projects - Thematic Grants
FAPESP's process: 08/57721-3 - Redoxome
Grantee:Ohara Augusto
Support type: Research Projects - Thematic Grants
FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
Grantee:Alicia Juliana Kowaltowski
Support type: Research Projects - Thematic Grants
FAPESP's process: 08/57952-5 - National Institute of Obesity and Diabetes
Grantee:Mario Jose Abdalla Saad
Support type: 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 type: Research Projects - Thematic Grants