Functioning of oxidative phosphorylation in liver mitochondria of high-fat diet fed rats

J. Ciapaite, S.J. Bakker, G. van Eikenhorst, M.J. Wagner, T. Teerlink, C.G. Schalkwijk, M. Fodor, DM. Ouwens, M. Diamant, R.J. Heine, H.V. Westerhoff, K. Krab

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)307-316
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Issue number3
Publication statusPublished - 1 Jan 2007

Cite this

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.