Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells
Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations....
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Stefano Bartesaghi [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 4, Seite 1059-1064 |
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| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:4 ; pages:1059-1064 |
| Links: |
Volltext |
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| DOI / URN: |
10.1073/pnas.1413165112 |
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| Katalog-ID: |
OLC1961708310 |
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| 245 | 1 | 0 | |a Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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| 520 | |a Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. | ||
| 540 | |a Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences | ||
| 650 | 4 | |a Neural Stem Cells - metabolism | |
| 650 | 4 | |a Glioma - metabolism | |
| 650 | 4 | |a Neural Stem Cells - pathology | |
| 650 | 4 | |a Tumor Suppressor Protein p53 - genetics | |
| 650 | 4 | |a Cell Transformation, Neoplastic - metabolism | |
| 650 | 4 | |a Citric Acid Cycle - genetics | |
| 650 | 4 | |a Electron Transport Chain Complex Proteins - genetics | |
| 650 | 4 | |a Brain Neoplasms - genetics | |
| 650 | 4 | |a Glioma - genetics | |
| 650 | 4 | |a Cell Transformation, Neoplastic - genetics | |
| 650 | 4 | |a Electron Transport Chain Complex Proteins - metabolism | |
| 650 | 4 | |a Brain Neoplasms - pathology | |
| 650 | 4 | |a Glioma - pathology | |
| 650 | 4 | |a Glycolysis - genetics | |
| 650 | 4 | |a Cell Transformation, Neoplastic - pathology | |
| 650 | 4 | |a Brain Neoplasms - metabolism | |
| 650 | 4 | |a Tumor Suppressor Protein p53 - metabolism | |
| 650 | 4 | |a Research | |
| 650 | 4 | |a Reactive oxygen species | |
| 650 | 4 | |a Gene mutations | |
| 650 | 4 | |a Analysis | |
| 650 | 4 | |a Stem cell research | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Mitochondrial DNA | |
| 650 | 4 | |a Stem cells | |
| 650 | 4 | |a Tumorigenesis | |
| 650 | 4 | |a Tumors | |
| 650 | 4 | |a Rodents | |
| 650 | 4 | |a Metabolism | |
| 650 | 4 | |a Genomics | |
| 650 | 4 | |a mitochondrial metabolism | |
| 650 | 4 | |a brain cancer | |
| 650 | 4 | |a p53 | |
| 650 | 4 | |a Biological Sciences | |
| 700 | 0 | |a Vincenzo Graziano |4 oth | |
| 700 | 0 | |a Sara Galavotti |4 oth | |
| 700 | 0 | |a Nick V. Henriquez |4 oth | |
| 700 | 0 | |a Joanne Betts |4 oth | |
| 700 | 0 | |a Jayeta Saxena |4 oth | |
| 700 | 0 | |a Deli A |4 oth | |
| 700 | 0 | |a Anna Karlsson |4 oth | |
| 700 | 0 | |a L. Miguel Martins |4 oth | |
| 700 | 0 | |a Melania Capasso |4 oth | |
| 700 | 0 | |a Pierluigi Nicotera |4 oth | |
| 700 | 0 | |a Sebastian Brandner |4 oth | |
| 700 | 0 | |a Vincenzo De Laurenzi |4 oth | |
| 700 | 0 | |a Paolo Salomoni |4 oth | |
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10.1073/pnas.1413165112 doi PQ20160617 (DE-627)OLC1961708310 (DE-599)GBVOLC1961708310 (PRQ)c3718-bb59af51dda90ba13d3278693b59de6a747f8bbdd35214fcd9e960ecf4d6429d3 (KEY)0583363920150000112000401059inhibitionofoxidativemetabolismleadstop53geneticin DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Stefano Bartesaghi verfasserin aut Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences Vincenzo Graziano oth Sara Galavotti oth Nick V. Henriquez oth Joanne Betts oth Jayeta Saxena oth Deli A oth Anna Karlsson oth L. Miguel Martins oth Melania Capasso oth Pierluigi Nicotera oth Sebastian Brandner oth Vincenzo De Laurenzi oth Paolo Salomoni oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 4, Seite 1059-1064 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:4 pages:1059-1064 http://dx.doi.org/10.1073/pnas.1413165112 Volltext http://www.pnas.org/content/112/4/1059.abstract http://www.ncbi.nlm.nih.gov/pubmed/25583481 http://search.proquest.com/docview/1650648604 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4313844&tool=pmcentrez&rendertype=abstract http://kipublications.ki.se/Default.aspx?queryparsed=id:130640527 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 4 1059-1064 |
| spelling |
10.1073/pnas.1413165112 doi PQ20160617 (DE-627)OLC1961708310 (DE-599)GBVOLC1961708310 (PRQ)c3718-bb59af51dda90ba13d3278693b59de6a747f8bbdd35214fcd9e960ecf4d6429d3 (KEY)0583363920150000112000401059inhibitionofoxidativemetabolismleadstop53geneticin DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Stefano Bartesaghi verfasserin aut Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences Vincenzo Graziano oth Sara Galavotti oth Nick V. Henriquez oth Joanne Betts oth Jayeta Saxena oth Deli A oth Anna Karlsson oth L. Miguel Martins oth Melania Capasso oth Pierluigi Nicotera oth Sebastian Brandner oth Vincenzo De Laurenzi oth Paolo Salomoni oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 4, Seite 1059-1064 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:4 pages:1059-1064 http://dx.doi.org/10.1073/pnas.1413165112 Volltext http://www.pnas.org/content/112/4/1059.abstract http://www.ncbi.nlm.nih.gov/pubmed/25583481 http://search.proquest.com/docview/1650648604 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4313844&tool=pmcentrez&rendertype=abstract http://kipublications.ki.se/Default.aspx?queryparsed=id:130640527 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 4 1059-1064 |
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10.1073/pnas.1413165112 doi PQ20160617 (DE-627)OLC1961708310 (DE-599)GBVOLC1961708310 (PRQ)c3718-bb59af51dda90ba13d3278693b59de6a747f8bbdd35214fcd9e960ecf4d6429d3 (KEY)0583363920150000112000401059inhibitionofoxidativemetabolismleadstop53geneticin DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Stefano Bartesaghi verfasserin aut Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences Vincenzo Graziano oth Sara Galavotti oth Nick V. Henriquez oth Joanne Betts oth Jayeta Saxena oth Deli A oth Anna Karlsson oth L. Miguel Martins oth Melania Capasso oth Pierluigi Nicotera oth Sebastian Brandner oth Vincenzo De Laurenzi oth Paolo Salomoni oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 4, Seite 1059-1064 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:4 pages:1059-1064 http://dx.doi.org/10.1073/pnas.1413165112 Volltext http://www.pnas.org/content/112/4/1059.abstract http://www.ncbi.nlm.nih.gov/pubmed/25583481 http://search.proquest.com/docview/1650648604 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4313844&tool=pmcentrez&rendertype=abstract http://kipublications.ki.se/Default.aspx?queryparsed=id:130640527 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 4 1059-1064 |
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10.1073/pnas.1413165112 doi PQ20160617 (DE-627)OLC1961708310 (DE-599)GBVOLC1961708310 (PRQ)c3718-bb59af51dda90ba13d3278693b59de6a747f8bbdd35214fcd9e960ecf4d6429d3 (KEY)0583363920150000112000401059inhibitionofoxidativemetabolismleadstop53geneticin DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Stefano Bartesaghi verfasserin aut Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences Vincenzo Graziano oth Sara Galavotti oth Nick V. Henriquez oth Joanne Betts oth Jayeta Saxena oth Deli A oth Anna Karlsson oth L. Miguel Martins oth Melania Capasso oth Pierluigi Nicotera oth Sebastian Brandner oth Vincenzo De Laurenzi oth Paolo Salomoni oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 4, Seite 1059-1064 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:4 pages:1059-1064 http://dx.doi.org/10.1073/pnas.1413165112 Volltext http://www.pnas.org/content/112/4/1059.abstract http://www.ncbi.nlm.nih.gov/pubmed/25583481 http://search.proquest.com/docview/1650648604 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4313844&tool=pmcentrez&rendertype=abstract http://kipublications.ki.se/Default.aspx?queryparsed=id:130640527 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 4 1059-1064 |
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10.1073/pnas.1413165112 doi PQ20160617 (DE-627)OLC1961708310 (DE-599)GBVOLC1961708310 (PRQ)c3718-bb59af51dda90ba13d3278693b59de6a747f8bbdd35214fcd9e960ecf4d6429d3 (KEY)0583363920150000112000401059inhibitionofoxidativemetabolismleadstop53geneticin DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Stefano Bartesaghi verfasserin aut Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences Vincenzo Graziano oth Sara Galavotti oth Nick V. Henriquez oth Joanne Betts oth Jayeta Saxena oth Deli A oth Anna Karlsson oth L. Miguel Martins oth Melania Capasso oth Pierluigi Nicotera oth Sebastian Brandner oth Vincenzo De Laurenzi oth Paolo Salomoni oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 4, Seite 1059-1064 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:4 pages:1059-1064 http://dx.doi.org/10.1073/pnas.1413165112 Volltext http://www.pnas.org/content/112/4/1059.abstract http://www.ncbi.nlm.nih.gov/pubmed/25583481 http://search.proquest.com/docview/1650648604 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4313844&tool=pmcentrez&rendertype=abstract http://kipublications.ki.se/Default.aspx?queryparsed=id:130640527 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 4 1059-1064 |
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Stefano Bartesaghi ddc 500 ddc 570 fid LING fid BIODIV misc Neural Stem Cells - metabolism misc Glioma - metabolism misc Neural Stem Cells - pathology misc Tumor Suppressor Protein p53 - genetics misc Cell Transformation, Neoplastic - metabolism misc Citric Acid Cycle - genetics misc Electron Transport Chain Complex Proteins - genetics misc Brain Neoplasms - genetics misc Glioma - genetics misc Cell Transformation, Neoplastic - genetics misc Electron Transport Chain Complex Proteins - metabolism misc Brain Neoplasms - pathology misc Glioma - pathology misc Glycolysis - genetics misc Cell Transformation, Neoplastic - pathology misc Brain Neoplasms - metabolism misc Tumor Suppressor Protein p53 - metabolism misc Research misc Reactive oxygen species misc Gene mutations misc Analysis misc Stem cell research misc Genetics misc Mitochondrial DNA misc Stem cells misc Tumorigenesis misc Tumors misc Rodents misc Metabolism misc Genomics misc mitochondrial metabolism misc brain cancer misc p53 misc Biological Sciences Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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500 DNB 570 AVZ LING fid BIODIV fid Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells Neural Stem Cells - metabolism Glioma - metabolism Neural Stem Cells - pathology Tumor Suppressor Protein p53 - genetics Cell Transformation, Neoplastic - metabolism Citric Acid Cycle - genetics Electron Transport Chain Complex Proteins - genetics Brain Neoplasms - genetics Glioma - genetics Cell Transformation, Neoplastic - genetics Electron Transport Chain Complex Proteins - metabolism Brain Neoplasms - pathology Glioma - pathology Glycolysis - genetics Cell Transformation, Neoplastic - pathology Brain Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism Research Reactive oxygen species Gene mutations Analysis Stem cell research Genetics Mitochondrial DNA Stem cells Tumorigenesis Tumors Rodents Metabolism Genomics mitochondrial metabolism brain cancer p53 Biological Sciences |
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ddc 500 ddc 570 fid LING fid BIODIV misc Neural Stem Cells - metabolism misc Glioma - metabolism misc Neural Stem Cells - pathology misc Tumor Suppressor Protein p53 - genetics misc Cell Transformation, Neoplastic - metabolism misc Citric Acid Cycle - genetics misc Electron Transport Chain Complex Proteins - genetics misc Brain Neoplasms - genetics misc Glioma - genetics misc Cell Transformation, Neoplastic - genetics misc Electron Transport Chain Complex Proteins - metabolism misc Brain Neoplasms - pathology misc Glioma - pathology misc Glycolysis - genetics misc Cell Transformation, Neoplastic - pathology misc Brain Neoplasms - metabolism misc Tumor Suppressor Protein p53 - metabolism misc Research misc Reactive oxygen species misc Gene mutations misc Analysis misc Stem cell research misc Genetics misc Mitochondrial DNA misc Stem cells misc Tumorigenesis misc Tumors misc Rodents misc Metabolism misc Genomics misc mitochondrial metabolism misc brain cancer misc p53 misc Biological Sciences |
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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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Stefano Bartesaghi |
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inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. |
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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. |
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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. |
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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells |
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