Expression of transforming K-Ras oncogene affects mitochondrial function and morphology in mouse fibroblasts.
K-ras transformed fibroblasts have been shown to have a stronger dependence from glycolysis, reduced oxidative phosphorylation ability and a fragility towards glucose depletion compared to their immortalized, normal counterparts. In this paper, using RNA profiling assays and metabolic perturbations, we report changes in expression of genes encoding mitochondrial proteins and alterations in mitochondrial morphology that correlate with mitochondrial functionality. In fact, unlike normal cells, transformed cells show reduced ATP content and inability to modify mitochondria morphology upon glucose depletion. Being reverted by GEF-DN expression, such morphological and functional changes are directly connected to Ras activation. Taken together with reported partial mitochondrial uncoupling and more sustained apoptosis of transformed cells, our results indicate that activation of the Ras pathway strikingly impacts on energy and signaling-related aspects of mitochondria functionality, that in turn may affect the terminal phenotype of transformed cells.
Chiaradonna
Ferdinando
F
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy. ferdinando.chiaradonna@unimib.it
Gaglio
Daniela
D
Vanoni
Marco
M
Alberghina
Lilia
L
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D015870:Gene Expression; D020869:Gene Expression Profiling; D005799:Genes, Dominant / Q000235:genetics; D050259:Genes, Mitochondrial / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics; D008954:Models, Biological; D020666:ras-GRF1 / Q000378:metabolism
D024101:Mitochondrial Proteins; D020666:ras-GRF1; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate; D005947:Glucose