La mitocondria: un nuevo paradigma en oncología

La revitalización del metabolismo energético en la biología del cáncer ha experimentado un fuerte impulso en los últimos años habiéndose establecido una estrecha relación de éste con los genes clásicos del cáncer. Sin embargo, el papel que desempeña la actividad bioenergética de la mitocondria en la progresión de la enfermedad es tema actual de debate. La reprogramación metabólica de las células cancerígenas es una característica fenotípica necesaria para la proliferación y supervivencia celular. Estudios recientes han demostrado a nivel transcriptómico, proteómico y funcional que la progresión del cáncer requiere, inevitablemente, la selección de las células cancerígenas que presentan una elevada actividad glucolítica debido a la represión bioenergética de sus mitocondrias. La huella bioenergética estimada por la razón entre las proteínas β-F1-ATPasa y GAPDH es un índice proteómico que informa de la actividad metabólica de los tumores y células cancerígenas y permite estimar la agresividad tumoral. Además, la huella bioenergética proporciona una diana común a neoplasias muy diversas para el desarrollo de nuevas terapias antitumorales ya que informa de la resistencia de las células cancerígenas a la quimioterapia. En este artículo de revisión destacamos los diferentes mecanismos que pueden alterar la actividad bioenergética de la mitocondria en cáncer, especialmente aquellos que afectan a la H+-ATP sintasa y que promueven el fenotipo Warburg de las células cancerígenas

Mitochondria-mediated energy adaption in cancer: The H+-ATP synthase-geared switch of metabolism in human tumors

Significance: Since the signing of the National Cancer Act in 1971, cancer still remains a major cause of death despite significant progresses made in understanding the biology and treatment of the disease. After many years of ostracism, the peculiar energy metabolism of tumors has been recognized as an additional phenotypic trait of the cancer cell. Recent Advances: While the enhanced aerobic glycolysis of carcinomas has already been translated to bedside for precise tumor imaging and staging of cancer patients, accepting that an impaired bioenergetic function of mitochondria is pivotal to understand energy metabolism of tumors and in its progression is debated. However, mitochondrial bioenergetics and cell death are tightly connected. Critical Issues: Recent clinical findings indicate that H+-ATP synthase, a core component of mitochondrial oxidative phosphorylation, is repressed at both the protein and activity levels in human carcinomas. This review summarizes the relevance that mitochondrial function has to understand energy metabolism of tumors and explores the connection between the bioenergetic function of the organelle and the activity of mitochondria as tumor suppressors. Future Directions: The reversible nature of energy metabolism in tumors highlights the relevance that the microenvironment has for tumor progression. Moreover, the stimulation of mitochondrial activity or the inhibition of glycolysis suppresses tumor growth. Future research should elucidate the mechanisms promoting the silencing of oxidative phosphorylation in carcinomas. The aim is the development of new therapeutic strategies tackling energy metabolism to eradicate tumors or at least, to maintain tumor dormancy and transform cancer into a chronic disease. Antioxid. Redox Signal. 19, 285-298Supported by JCI2009-03918 Juan de la Cierva Grant, Ministerio de Educación y Ciencia, Spain. Work in the authors’ laboratory was supported by grants from the Ministerio de Educación y Ciencia (BFU2010-18903), by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII and by Comunidad de Madrid (S2011/BMD-2402), Spain. The CBMSO receives an institutional grant from Fundación Ramón Arece

AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells

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.</jats:p

Excitonic couplings between molecular crystal pairs by a multistate approximation

In this paper, we present a diabatization scheme to compute the excitonic couplings between an arbitrary number of states in molecular pairs. The method is based on an algebraic procedure to find the diabatic states with a desired property as close as possible to that of some reference states. In common with other diabatization schemes, this method captures the physics of the important short-range contributions (exchange, overlap, and charge-transfer mediated terms) but it becomes particularly suitable in presence of more than two states of interest. The method is formulated to be usable with any level of electronic structure calculations and to diabatize different types of states by selecting different molecular properties. These features make the diabatization scheme presented here especially appropriate in the context of organic crystals, where several excitons localized on the same molecular pair may be found close in energy. In this paper, the method is validated on the tetracene crystal dimer, a well characterized case where the charge transfer (CT) states are closer in energy to the Frenkel excitons (FE). The test system was studied as a function of an external electric field (to explore the effect of changing the relative energy of the CT excited state) and as a function of different intermolecular distances (to probe the strength of the coupling between FE and CT states). Additionally, we illustrate how the approximation can be used to include the environment polarization effect

Poling effect on distribution of quenched random fields in a uniaxial relaxor ferroelectric

The frequency dependence of the dielectric permitivity's maximum has been studied for poled and unpoled doped relaxor strontium barium niobate $Sr_{0.61}Ba_{0.39}Nb_{2}O_{6}:Cr^{3+}$ (SBN-61:Cr). In both cases the maximum found is broad and the frequency dispersion is strong. The present view of random fields compensation in the unpoled sample is not suitable for explaining this experimental result. We propose a new mechanism where the dispersion of quenched random electric fields, affecting the nanodomains, is minimized after poling. We test our proposal by numerical simulations on a random field Ising model. Results obtained are in agreement with the polarization's measurements presented by Granzow et al. [Phys. Rev. Lett {\bf 92}, 065701 (2004)].Comment: 7 pages, 4 figure