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 diseas...

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Main Authors: Mateus P. Mori, Rute A. P. Costa, Daniela T. Soltys, Thiago de S. Freire, Franco A. Rossato, Ignácio Amigo, Alicia J. Kowaltowski, Aníbal E. Vercesi, Nadja C. de Souza-Pinto
Format: Article
Language:English
Published: Nature Publishing Group 2017-03-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-017-00130-x
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spelling doaj-8c3abd91e76c4e26a1355a84576051ac2020-12-08T02:05:33ZengNature Publishing GroupScientific Reports2045-23222017-03-017111510.1038/s41598-017-00130-xLack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stressMateus P. Mori0Rute A. P. Costa1Daniela T. Soltys2Thiago de S. Freire3Franco A. Rossato4Ignácio Amigo5Alicia J. Kowaltowski6Aníbal E. Vercesi7Nadja C. de Souza-Pinto8Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)Department of Clinical Pathology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP)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.https://doi.org/10.1038/s41598-017-00130-x
collection DOAJ
language English
format Article
sources DOAJ
author Mateus P. Mori
Rute A. P. Costa
Daniela T. Soltys
Thiago de S. Freire
Franco A. Rossato
Ignácio Amigo
Alicia J. Kowaltowski
Aníbal E. Vercesi
Nadja C. de Souza-Pinto
spellingShingle Mateus P. Mori
Rute A. P. Costa
Daniela T. Soltys
Thiago de S. Freire
Franco A. Rossato
Ignácio Amigo
Alicia J. Kowaltowski
Aníbal E. Vercesi
Nadja C. de Souza-Pinto
Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
Scientific Reports
author_facet Mateus P. Mori
Rute A. P. Costa
Daniela T. Soltys
Thiago de S. Freire
Franco A. Rossato
Ignácio Amigo
Alicia J. Kowaltowski
Aníbal E. Vercesi
Nadja C. de Souza-Pinto
author_sort Mateus P. Mori
title Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
title_short Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
title_full Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
title_fullStr Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
title_full_unstemmed Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
title_sort lack of xpc leads to a shift between respiratory complexes i and ii but sensitizes cells to mitochondrial stress
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2017-03-01
description 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.
url https://doi.org/10.1038/s41598-017-00130-x
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