Human Molecular Genetics Advance Access originally published online on March 6, 2007
Human Molecular Genetics 2007 16(8):993-1005; doi:10.1093/hmg/ddm045
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PGC-1
/ß upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations
1 Department of Neurology, 2 Department of Physiology & Biophysics and 3 Department of Cell Biology & Anatomy, University of Miami, Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
* To whom correspondence should be addressed at: Tel: +1 3052435858; Fax: +1 3052433914; Email: cmoraes{at}med.miami.edu
Received November 29, 2006; Accepted February 26, 2007
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-1
and PGC-1ß transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviral-mediated overexpression of PGC-1 and PGC-1ß in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1/ß coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1 and PGC-1ß in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.