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PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations

Oncogene volume 32, pages 2592–2600 (2013)Cite this article

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Abstract

Primary mitochondrial dysfunction commonly leads to failure in cellular adaptation to stress. Paradoxically, however, nonsynonymous mutations of mitochondrial DNA (mtDNA) are frequently found in cancer cells and may have a causal role in the development of resistance to genotoxic stress induced by common chemotherapeutic agents, such as cis-diammine-dichloroplatinum(II) (cisplatin, CDDP). Little is known about how these mutations arise and the associated mechanisms leading to chemoresistance. Here, we show that the development of adaptive chemoresistance in the A549 non-small-cell lung cancer cell line to CDDP is associated with the hetero- to homoplasmic shift of a nonsynonymous mutation in MT-ND2, encoding the mitochondrial Complex-I subunit ND2. The mutation resulted in a 50% reduction of the NADH:ubiquinone oxidoreductase activity of the complex, which was compensated by increased biogenesis of respiratory chain complexes. The compensatory mitochondrial biogenesis was most likely mediated by the nuclear co-activators peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) and PGC-1β, both of which were significantly upregulated in the CDDP-resistant cells. Importantly, both transient and stable silencing of PGC-1β re-established the sensitivity of these cells to CDDP-induced apoptosis. Remarkably, the PGC-1β-mediated CDDP resistance was independent of the mitochondrial effects of the co-activator. Altogether, our results suggest that partial respiratory chain defects because of mtDNA mutations can lead to compensatory upregulation of nuclear transcriptional co-regulators, in turn mediating resistance to genotoxic stress.

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Acknowledgements

We thank the excellent technical help of M Rahman (UCL Biosciences Molecular Biology Unit), K Pearce (UCL Genomics), the access to the Arrayscan VTI HCS Reader and the help of G Keen, M Elrayess and J Staddon from Eisai Europe Ltd; Professors M Duchen, C Boshoff and JM Funes for reagents and advice; JW Taanman for providing the A549 rho0 cell line, and D Housenloy for the Akt antibodies. The work was supported by Parkinson’s UK (G-0905) and the Medical Research Council (MRC-DTA) to GS, ZY and AJ MRW is supported by the Polish Ministry of Science and Higher Education under Grant NN407075137 and by the grant from the National Science Centre—decision number DEC-2011/01/M/NZ3/02128. JMS is a recipient of a PhD fellowship from the Foundation for Polish Science, EU, European Regional Development Fund and Operational Programme “Innovative economy”. ML is recipient of a fellowship from the Foundation for Polish Science (Programme Start) and the L’Oreal fellowship (For Women in Science). SR is supported by Great Ormond Street Hospital Children’s Charity. GK is supported by the European Union (ApoSys, ArtForce, ChemoRes) and the Ligue contre le Cancer (Laboratoire labellisé).

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Author notes

  1. A W E Jones

    Present address: 15Current address: The Wolfson Institute for Biomedical Research, University College London, London, UK,

  2. Z Yao and A W E Jones: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK

    Z Yao, A W E Jones & G Szabadkai

  2. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    E Fassone & S Rahman

  3. Department of Neurological Sciences, Dino Ferrari Centre, University of Milan, IRCCS Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

    E Fassone

  4. Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK

    M G Sweeney

  5. Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland

    M Lebiedzinska, J M Suski & M R Wieckowski

  6. INSERM, U848, Institut Gustave Roussy, Villejuif, France

    N Tajeddine & G Kroemer

  7. Institute of Neurology, University College London, London, UK

    I P Hargreaves

  8. The Wolfson Institute for Biomedical Research, University College London, London, UK

    T Yasukawa

  9. Université Paris-Sud, INSERM UMR-S 769, Châtenay-Malabry, France

    G Tufo & C Brenner

  10. Metabolomics Platform, Institut Gustave Roussy, Pavillon de Recherche 1, Villejuif, France

    G Kroemer

  11. Centre de Recherche des Cordeliers, Paris, France

    G Kroemer

  12. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

  13. Université Paris Descartes, Faculté de Médecine, Paris, France

    G Kroemer

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  1. Z Yao
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Correspondence to G Szabadkai.

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Yao, Z., Jones, A., Fassone, E. et al. PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations. Oncogene 32, 2592–2600 (2013). https://doi.org/10.1038/onc.2012.259

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  • DOI: https://doi.org/10.1038/onc.2012.259

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