title: Functioning of oxidative phosphorylation in liver mitochondria of high-fat diet fed rats.
abstract: 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.
authors.affiliation: Department of Molecular Cell Physiology, Institute for Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands. jolita.ciapaite@falw.vu.nl
authors.forename: Jolita
authors.initials: J
authors.lastname: Ciapaite
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Gerco
authors.initials: G
authors.lastname: Van Eikenhorst
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Mariann
authors.initials: M
authors.lastname: Fodor
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
authors.forename: Klaas
authors.initials: K
authors.lastname: Krab
mesh_terms: D033781:Adenine Nucleotide Translocator 3 / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage*; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D051381:Rats
chemical_list: D033781:Adenine Nucleotide Translocator 3; D004041:Dietary Fats; C048496:N(6)-carboxymethyllysine; D000255:Adenosine Triphosphate; D008239:Lysine