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Grant support

This work was supported by grants SAF2013-48626-C2-1-R and SAF2016-76338-R from Ministerio de Economia y Competitividad (MINECO) to AA, by the PRT-K program 2018 to MV and by Gobierno de Aragon (Group B31_17R) cofinanced by Feder 2014-2020 "Building Europe from Aragon". JMB was supported by an EMBO short-term fellowship and by PHISIUP.

Analysis of institutional authors

Marco-Brualla, JoaquinAuthor

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May 29, 2025
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Mutations in the ND2 Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells

Publicated to:Cancers. 11 (7): 1027- - 2019-06-26 11(7), DOI: 10.3390/cancers11071027

Authors: Marco-Brualla, Joaquin; Al-Wasaby, Sameer; Soler, Ruth; Romanos, Eduardo; Conde, Blanca; Justo-Mendez, Raquel; Enriquez, Jose A; Fernandez-Silva, Patricio; Martinez-Lostao, Luis; Villalba, Martin; Moreno-Loshuertos, Raquel; Anel, Alberto

Affiliations

Aragon Hlth Res Inst IIS Aragon, Ctr Res Biomed, E-50009 Zaragoza, Spain - Author
Carlos III Natl Ctr Cardiovasc Res, Madrid 28029, Spain - Author
CHU Montpellier, IRMB, F-34090 Montpellier, France - Author
Lozano Blesa Clin Hosp, Immunol Dept, E-50009 Zaragoza, Spain - Author
Univ Montpellier, CHU Montpellier, Natl Inst Biomed Res INSERM, Inst Regenerat Med & Biotherapy, F-34090 Montpellier, France - Author
Univ Zaragoza, Dept Human Anat & Histol, Fac Med, Campus San Francisco Sq, E-50009 Zaragoza, Spain - Author
Univ Zaragoza, Fac Sci, Aragon Hlth Res Inst IIS Aragon, Immun Canc & Stem Cells Grp,Dept Biochem & Mol &, Campus San Francisco Sq, E-50009 Zaragoza, Spain - Author
Univ Zaragoza, Fac Sci, Dept Biochem & Mol & Cell Biol, GENOXPHOS Grp,Biocomputat & Complex Syst Phys Ins, Campus San Francisco Sq, E-50009 Zaragoza, Spain - Author
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Abstract

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 ND2 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.

Keywords

Complex iContributeCybridCybridsDichloroacetateDna mutationsErk5ExpressionGenerationHeaMetabolismMetastasisMhc class-iMitochondriaNd2

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancers due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2019, it was in position 37/244, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 5.7, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-04, the following number of citations:

  • WoS: 24
  • Scopus: 26
  • Europe PMC: 17

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 33.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 35 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.25.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Marco Brualla, Joaquín) .