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Glucose-Modulated Mitochondria Adaptation in Tumor Cells: A Focus on ATP Synthase and Inhibitor Factor 1
Department of Medical and Biological Sciences, University of Udine, p.le Kolbe 4, 33100 Udine, Italy
M.A.T.I. Centre of Excellence, University of Udine, p.le Kolbe 4, 33100 Udine, Italy
* Author to whom correspondence should be addressed.
Received: 31 October 2011; in revised form: 6 January 2012 / Accepted: 30 January 2012 / Published: 10 February 2012
Abstract: Warburg’s hypothesis has been challenged by a number of studies showing that oxidative phosphorylation is repressed in some tumors, rather than being inactive per se. Thus, treatments able to shift energy metabolism by activating mitochondrial pathways have been suggested as an intriguing basis for the optimization of antitumor strategies. In this study, HepG2 hepatocarcinoma cells were cultivated with different metabolic substrates under conditions mimicking “positive” (activation/biogenesis) or “negative” (silencing) mitochondrial adaptation. In addition to the expected up-regulation of mitochondrial biogenesis, glucose deprivation caused an increase in phosphorylating respiration and a rise in the expression levels of the ATP synthase β subunit and Inhibitor Factor 1 (IF1). Hyperglycemia, on the other hand, led to a markedly decreased level of the transcriptional coactivator PGC-α suggesting down-regulation of mitochondrial biogenesis, although no change in mitochondrial mass and no impairment of phosphorylating respiration were observed. Moreover, a reduction in mitochondrial networking and in ATP synthase dimer stability was produced. No effect on β-ATP synthase expression was elicited. Notably, hyperglycemia caused an increase in IF1 expression levels, but it did not alter the amount of IF1 associated with ATP synthase. These results point to a new role of IF1 in relation to high glucose utilization by tumor cells, in addition to its well known effect upon mitochondrial ATP synthase regulation.
Keywords: ATP synthase; inhibitory factor 1; metabolic adaptation; tumor bioenergetics; hyperglycemia; aglycemia; mitochondria; oxidative phosphorylation; HepG2
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Domenis, R.; Bisetto, E.; Rossi, D.; Comelli, M.; Mavelli, I. Glucose-Modulated Mitochondria Adaptation in Tumor Cells: A Focus on ATP Synthase and Inhibitor Factor 1. Int. J. Mol. Sci. 2012, 13, 1933-1950.
Domenis R, Bisetto E, Rossi D, Comelli M, Mavelli I. Glucose-Modulated Mitochondria Adaptation in Tumor Cells: A Focus on ATP Synthase and Inhibitor Factor 1. International Journal of Molecular Sciences. 2012; 13(2):1933-1950.
Domenis, Rossana; Bisetto, Elena; Rossi, Davide; Comelli, Marina; Mavelli, Irene. 2012. "Glucose-Modulated Mitochondria Adaptation in Tumor Cells: A Focus on ATP Synthase and Inhibitor Factor 1." Int. J. Mol. Sci. 13, no. 2: 1933-1950.