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

Z. Yao, A. W.E. Jones, E. Fassone, M. G. Sweeney, M. Lebiedzinska, J. M. Suski, M. R. Wieckowski, N. Tajeddine, I. P. Hargreaves, T. Yasukawa, G. Tufo, C. Brenner, G. Kroemer, S. Rahman, G. Szabadkai

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2592-2600
Number of pages9
JournalOncogene
Volume32
Issue number20
DOIs
Publication statusPublished - May 16 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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