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.
Highlights
The most popular paradigm of metabolic remodelling describing the occurrence in tumor cells comprises an increase in glucose uptake, an enhancement of glycolytic capacity, high lactate production, and the absence of respiration caused by irreversible damage to mitochondrial function [1]
To investigate whether the supramolecular organization of ATP synthase was affected by the bioenergetic adaptation of mitochondria and whether the increase in Inhibitor Factor 1 (IF1) expression level was correlated with ATP synthase oligomer stability, we used blue native gel (BNE) to analyze mitochondria isolated from
Aglycemic culture conditions stimulated mitochondrial activity in HepG2 cells as a result of increased mitochondrial mass and oxidative phosphorylation (OXPHOS) protein expression levels, demonstrating the OXPHOS system to play an important role in energy production and cell viability under glucose–limiting conditions
Summary
Rossana Domenis 1,2, Elena Bisetto 1,2, Davide Rossi 1,2, Marina Comelli 1,2 and Irene Mavelli 1,2,*. M.A.T.I. Centre of Excellence, University of Udine, p.le Kolbe 4, 33100 Udine, Italy. Received: 31 October 2011; in revised form: 6 January 2012 / Accepted: 30 January 2012 /
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