PGC-1alpha/beta 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-1alpha and PGC-1beta transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviral-mediated overexpression of PGC-1alpha and PGC-1beta in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1alpha/beta coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1alpha and PGC-1beta in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.
Srivastava
Sarika
S
Department of Neurology, University of Miami, Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
Barrett
John N
JN
Moraes
Carlos T
CT
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D019069:Cell Respiration / Q000235:genetics; D018389:Codon, Nonsense; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D008954:Models, Biological; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D006360:Heat-Shock Proteins; D024101:Mitochondrial 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; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; C481838:MT-ND5 protein, human; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I