We proposed that inhibition of mitochondrial adenine nucleotide translocator (ANT) by long chain acyl-CoA (LCAC) underlies the mechanism associating obesity and type 2 diabetes. Here we test that after long-term exposure to a high-fat diet (HFD): (i) there is no adaptation of the mitochondrial compartment that would hinder such ANT inhibition, and (ii) ANT has significant control of the relevant aspects of oxidative phosphorylation. After 7 weeks, HFD induced a 24+/-6% increase in hepatic LCAC concentration and accumulation of the oxidative stress marker N(epsilon)-(carboxymethyl)lysine. HFD did not significantly affect mitochondrial copy number, oxygen uptake, membrane potential (Deltapsi), ADP/O ratio, and the content of coenzyme Q(9), cytochromes b and a+a(3). Modular kinetic analysis showed that the kinetics of substrate oxidation, phosphorylation, proton leak, ATP-production and ATP-consumption were not influenced significantly. After HFD-feeding ANT exerted considerable control over oxygen uptake (control coefficient C=0.14) and phosphorylation fluxes (C=0.15), extra- (C=0.23) and intramitochondrial (C=-0.56) ATP/ADP ratios, and Deltapsi (C=-0.11). We conclude that although HFD induces accumulation of LCAC and N(epsilon)-(carboxymethyl)lysine, oxidative phosphorylation does not adapt to these metabolic challenges. Furthermore, ANT retains control of fluxes and intermediates, making inhibition of this enzyme a more probable link between obesity and type 2 diabetes.
|Journal||Biochimica et Biophysica Acta-Molecular Basis of Disease|
|Publication status||Published - 1 Jan 2007|
Ciapaite, J., Bakker, S. J., van Eikenhorst, G., Wagner, M. J., Teerlink, T., Schalkwijk, C. G., Fodor, M., Ouwens, DM., Diamant, M., Heine, R. J., Westerhoff, H. V., & Krab, K. (2007). Functioning of oxidative phosphorylation in liver mitochondria of high-fat diet fed rats. Biochimica et Biophysica Acta-Molecular Basis of Disease, 1772(3), 307-316. https://doi.org/10.1016/j.bbadis.2006.10.018