PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations.
(2012) Oncogene : including Oncogene Reviews — Vol. 32, n° 20, p. 2592-2600 (2013)
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- 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.Oncogene advance online publication, 9 July 2012; doi:10.1038/onc.2012.259.
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Yao, Z., Jones, A. W. E., Fassone, E., Sweeney, M. G., Lebiedzinska, M., Suski, J. M., Wieckowski, M. R., Tajeddine, N., Hargreaves, I. P., Yasukawa, T., Tufo, G., Brenner, C., Kroemer, G., Rahman, S., & Szabadkai, G. (2012). PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations. Oncogene : including Oncogene Reviews, 32(20), 2592-2600. https://hdl.handle.net/2078.5/62925 (Original work published 2013)