title: Metabolic control of mitochondrial properties by adenine nucleotide translocator determines palmitoyl-CoA effects. Implications for a mechanism linking obesity and type 2 diabetes.
abstract: Inhibition of the mitochondrial adenine nucleotide translocator (ANT) by long-chain acyl-CoA esters has been proposed to contribute to cellular dysfunction in obesity and type 2 diabetes by increasing formation of reactive oxygen species and adenosine via effects on the coenzyme Q redox state, mitochondrial membrane potential (Deltapsi) and cytosolic ATP concentrations. We here show that 5 microm palmitoyl-CoA increases the ratio of reduced to oxidized coenzyme Q (QH(2)/Q) by 42 +/- 9%, Deltapsi by 13 +/- 1 mV (9%), and the intramitochondrial ATP/ADP ratio by 352 +/- 34%, and decreases the extramitochondrial ATP/ADP ratio by 63 +/- 4% in actively phosphorylating mitochondria. The latter reduction is expected to translate into a 24% higher extramitochondrial AMP concentration. Furthermore, palmitoyl-CoA induced concentration-dependent H(2)O(2) formation, which can only partly be explained by its effect on Deltapsi. Although all measured fluxes and intermediate concentrations were affected by palmitoyl-CoA, modular kinetic analysis revealed that this resulted mainly from inhibition of the ANT. Through Metabolic Control Analysis, we then determined to what extent the ANT controls the investigated mitochondrial properties. Under steady-state conditions, the ANT moderately controlled oxygen uptake (control coefficient C = 0.13) and phosphorylation (C = 0.14) flux. It controlled intramitochondrial (C = -0.70) and extramitochondrial ATP/ADP ratios (C = 0.23) more strongly, whereas the control exerted over the QH(2)/Q ratio (C = -0.04) and Deltapsi (C = -0.01) was small. Quantitative assessment of the effects of palmitoyl-CoA showed that the mitochondrial properties that were most strongly controlled by the ANT were affected the most. Our observations suggest that long-chain acyl-CoA esters may contribute to cellular dysfunction in obesity and type 2 diabetes through effects on cellular energy metabolism and production of reactive oxygen species.
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: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Gerco
authors.initials: G
authors.lastname: van Eikenhorst
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: D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D010171:Palmitoyl Coenzyme A; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D006861:Hydrogen Peroxide