title: AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells.
abstract: Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non-derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondrial function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigación Hospital 12 de Octubre, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martínez-Reyes
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Aragó
authors.forename: José M
authors.initials: JM
authors.lastname: Cuezva
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D001343:Autophagy / Q000502:physiology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018716:Molecular Mimicry / Q000502:physiology; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C497109:ATF4 protein, human; D004272:DNA, Mitochondrial; C539950:NR6A1 protein, human; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D051701:Activating Transcription Factor 4; D055372:AMP-Activated Protein Kinases