PGC-1α/β upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations

We have studied the functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. Surprisingly, these cells had an efficient oxidative phosphorylation (OXPHOS); however, when mitochondria from these cells were transferred to an osteosarcoma nuclear background (osteosarcoma cybrids), the rate of respiration markedly declined suggesting that the phenotypic expression of the mtDNA mutations was prevented by the colorectal tumor nuclear background. We found that there was a significant increase in the steady-state levels of PGC-1α and PGC-1β transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviralmediated overexpression of PGC-1α and PGC-1β in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1α/β coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1α and PGC-1β in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.