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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8c3abd91e76c4e26a1355a84576051ac
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spelling	oai:doaj.org-article:8c3abd91e76c4e26a1355a84576051ac2021-12-02T11:40:42ZLack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress10.1038/s41598-017-00130-x2045-2322https://doaj.org/article/8c3abd91e76c4e26a1355a84576051ac2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00130-xhttps://doaj.org/toc/2045-2322Abstract 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.Mateus P. MoriRute A. P. CostaDaniela T. SoltysThiago de S. FreireFranco A. RossatoIgnácio AmigoAlicia J. KowaltowskiAníbal E. VercesiNadja C. de Souza-PintoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2017
url	https://doaj.org/article/8c3abd91e76c4e26a1355a84576051ac
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_version_	1718395594231250944

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

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