title: PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations.
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.
authors: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors: Z
authors: Z
authors: Yao
authors: A W E
authors: AW
authors: Jones
authors: E
authors: E
authors: Fassone
authors: M G
authors: MG
authors: Sweeney
authors: M
authors: M
authors: Lebiedzinska
authors: J M
authors: JM
authors: Suski
authors: M R
authors: MR
authors: Wieckowski
authors: N
authors: N
authors: Tajeddine
authors: I P
authors: IP
authors: Hargreaves
authors: T
authors: T
authors: Yasukawa
authors: G
authors: G
authors: Tufo
authors: C
authors: C
authors: Brenner
authors: G
authors: G
authors: Kroemer
authors: S
authors: S
authors: Rahman
authors: G
authors: G
authors: Szabadkai
mesh_terms: D000222:Adaptation, Physiological; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004272:DNA, Mitochondrial; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human; D002945:Cisplatin