Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells.
Many cancer cells are characterized by high rate of glycolysis and reduced rate of aerobic respiration, whose mechanism is still elusive. Here we investigate the down-regulation of oxidative phosphorylation (OXPHOS) in K-ras transformed mouse fibroblasts as compared to a control counterpart. Transcriptional analysis showed different expression levels of several OXPHOS nuclear genes in the two cell lines. In particular, during the exponential growth phase most genes encoding proteins of Complex I were expressed at lower levels in transformed cells. Consistently, a significant decrease of Complex I content was found in transformed cells. Moreover, analysis of NAD-dependent respiration and ATP synthesis indicated a strong decrease of Complex I activity in the mitochondria from neoplastic cells, that was confirmed by direct assay of the enzyme redox activity. At variance, succinate-dependent respiration and ATP synthesis were not significantly affected. Taken together, our results provide the new insight that the reduction of respiration observed in K-ras transformed cells is specifically due to a Complex I activity decrease.
Baracca
Alessandra
A
Department of Biochemistry "G. Moruzzi", University of Bologna, Bologna, Italy.
Chiaradonna
Ferdinando
F
Sgarbi
Gianluca
G
Solaini
Giancarlo
G
Alberghina
Lilia
L
Lenaz
Giorgio
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D019069:Cell Respiration / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000378:metabolism*; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D011905:Genes, ras; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism
D015415:Biomarkers; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D010100:Oxygen