Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells
Multiprotein complexes of the mitochondrial electron transport chain form associations to generate supercomplexes. The relationship between tumor cell ability to assemble mitochondrial supercomplexes, tumorigenesis and metastasis has not been studied thoroughly. The mitochondrial and metabolic diffe...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/7/1027 |
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| author | Joaquín Marco-Brualla Sameer Al-Wasaby Ruth Soler Eduardo Romanos Blanca Conde Raquel Justo-Méndez José A. Enríquez Patricio Fernández-Silva Luis Martínez-Lostao Martín Villalba Raquel Moreno-Loshuertos Alberto Anel |
| author_facet | Joaquín Marco-Brualla Sameer Al-Wasaby Ruth Soler Eduardo Romanos Blanca Conde Raquel Justo-Méndez José A. Enríquez Patricio Fernández-Silva Luis Martínez-Lostao Martín Villalba Raquel Moreno-Loshuertos Alberto Anel |
| author_sort | Joaquín Marco-Brualla |
| collection | DOAJ |
| description | Multiprotein complexes of the mitochondrial electron transport chain form associations to generate supercomplexes. The relationship between tumor cell ability to assemble mitochondrial supercomplexes, tumorigenesis and metastasis has not been studied thoroughly. The mitochondrial and metabolic differences between L929dt cells, which lost matrix attachment and MHC-I expression, and their parental cell line L929, were analyzed. L929dt cells have lower capacity to generate energy through OXPHOS and lower respiratory capacity than parental L929 cells. Most importantly, L929dt cells show defects in mitochondrial supercomplex assembly, especially in those that contain complex I. These defects correlate with mtDNA mutations in L929dt cells at the <i>ND2</i> subunit of complex I and are accompanied by a glycolytic shift. In addition, L929dt cells show higher in vivo tumorigenic and metastatic potential than the parental cell line. Cybrids with L929dt mitochondria in L929 nuclear background reproduce all L929dt properties, demonstrating that mitochondrial mutations are responsible for the aggressive tumor phenotype. In spite of their higher tumorigenic potential, L929dt or mitochondrial L929dt cybrid cells are sensitive both in vitro and in vivo to the PDK1 inhibitor dichloroacetate, which favors OXPHOS, suggesting benefits for the use of metabolic inhibitors in the treatment of especially aggressive tumors. |
| first_indexed | 2024-03-12T08:05:48Z |
| format | Article |
| id | doaj.art-5714b53b0c31404bb81c071130c3413b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:05:48Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5714b53b0c31404bb81c071130c3413b2023-09-02T19:31:58ZengMDPI AGCancers2072-66942019-07-01117102710.3390/cancers11071027cancers11071027Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer CellsJoaquín Marco-Brualla0Sameer Al-Wasaby1Ruth Soler2Eduardo Romanos3Blanca Conde4Raquel Justo-Méndez5José A. Enríquez6Patricio Fernández-Silva7Luis Martínez-Lostao8Martín Villalba9Raquel Moreno-Loshuertos10Alberto Anel11Immunity, Cancer & Stem Cells Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Aragón Health Research Institute (IIS Aragón), University of Zaragoza, E-50009 Zaragoza, SpainImmunity, Cancer & Stem Cells Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Aragón Health Research Institute (IIS Aragón), University of Zaragoza, E-50009 Zaragoza, SpainImmunity, Cancer & Stem Cells Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Aragón Health Research Institute (IIS Aragón), University of Zaragoza, E-50009 Zaragoza, SpainAragón Health Research Institute (IIS Aragón), Center for Research in Biomedicine, E-50009 Zaragoza, SpainDepartment of Human Anatomy and Histology, Faculty of Medicine, Campus San Francisco Square, University of Zaragoza, E-50009 Zaragoza, SpainCarlos III National Center for Cardiovascular Research, 28029 Madrid, SpainCarlos III National Center for Cardiovascular Research, 28029 Madrid, SpainGENOXPHOS Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Biocomputation and Complex Systems Physics Institute (BIFI), University of Zaragoza, E-50009 Zaragoza, SpainImmunology Department, Lozano Blesa Clinical Hospital, E-50009 Zaragoza, SpainThe National Institute of Biomedical Research (INSERM), Centre Hospitalier Universitaire de Montpellier, The University of Montpellier, The Institute for Regenerative Medicine and Biotherapy, 34090 Montpellier, FranceGENOXPHOS Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Biocomputation and Complex Systems Physics Institute (BIFI), University of Zaragoza, E-50009 Zaragoza, SpainImmunity, Cancer & Stem Cells Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Square, Aragón Health Research Institute (IIS Aragón), University of Zaragoza, E-50009 Zaragoza, SpainMultiprotein complexes of the mitochondrial electron transport chain form associations to generate supercomplexes. The relationship between tumor cell ability to assemble mitochondrial supercomplexes, tumorigenesis and metastasis has not been studied thoroughly. The mitochondrial and metabolic differences between L929dt cells, which lost matrix attachment and MHC-I expression, and their parental cell line L929, were analyzed. L929dt cells have lower capacity to generate energy through OXPHOS and lower respiratory capacity than parental L929 cells. Most importantly, L929dt cells show defects in mitochondrial supercomplex assembly, especially in those that contain complex I. These defects correlate with mtDNA mutations in L929dt cells at the <i>ND2</i> subunit of complex I and are accompanied by a glycolytic shift. In addition, L929dt cells show higher in vivo tumorigenic and metastatic potential than the parental cell line. Cybrids with L929dt mitochondria in L929 nuclear background reproduce all L929dt properties, demonstrating that mitochondrial mutations are responsible for the aggressive tumor phenotype. In spite of their higher tumorigenic potential, L929dt or mitochondrial L929dt cybrid cells are sensitive both in vitro and in vivo to the PDK1 inhibitor dichloroacetate, which favors OXPHOS, suggesting benefits for the use of metabolic inhibitors in the treatment of especially aggressive tumors.https://www.mdpi.com/2072-6694/11/7/1027mitochondriadichloroacetatecomplex I<i>ND2</i>metastasiscybrids |
| spellingShingle | Joaquín Marco-Brualla Sameer Al-Wasaby Ruth Soler Eduardo Romanos Blanca Conde Raquel Justo-Méndez José A. Enríquez Patricio Fernández-Silva Luis Martínez-Lostao Martín Villalba Raquel Moreno-Loshuertos Alberto Anel Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells Cancers mitochondria dichloroacetate complex I <i>ND2</i> metastasis cybrids |
| title | Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells |
| title_full | Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells |
| title_fullStr | Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells |
| title_full_unstemmed | Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells |
| title_short | Mutations in the <i>ND2</i> Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells |
| title_sort | mutations in the i nd2 i subunit of mitochondrial complex i are sufficient to confer increased tumorigenic and metastatic potential to cancer cells |
| topic | mitochondria dichloroacetate complex I <i>ND2</i> metastasis cybrids |
| url | https://www.mdpi.com/2072-6694/11/7/1027 |
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