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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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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