Journal Article

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

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

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/726/2129 / 631/67/1059/2326 / 631/67/1612/1350 / Adaptation, Physiological / Apoptosis / Biosynthesis / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Biology / Cell Line, Tumor / Chemoresistance / Chemotherapy / Cisplatin / Cisplatin - pharmacology / DNA, Mitochondrial / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Electron transport / Evolution / Gene mutations / Genetic aspects / Genotoxicity / Heat-Shock Proteins - genetics / Heat-Shock Proteins - metabolism / Human Genetics / Humans / Internal Medicine / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Medicine / Medicine & Public Health / Mitochondrial DNA / Mutation / NADH / NADH Dehydrogenase - genetics / NADH-ubiquinone oxidoreductase / Non-small cell lung carcinoma / Oncology / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Physiological aspects / RNA-Binding Proteins / short-communication / Transcription / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional coactivators / Ubiquinone oxidoreductase