1. Metabolic control of mitochondrial properties by adenine nucleotide translocator determines palmitoyl-CoA effects.
- Author
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Ciapaite, Jolita, Bakker, Stephan J. L., Diamant, Michaela, van Eikenhorst, Gerco, Heine, Robert J., Westerhoff, Hans V., and Krab, Klaas
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PHOSPHORYLATION ,DIABETES ,ADENOSINES ,METABOLIC regulation ,ADENINE nucleotides - 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 (Δψ) and cytosolic ATP concentrations. We here show that 5 µm palmitoyl-CoA increases the ratio of reduced to oxidized coenzyme Q (QH
2 /Q) by 42 ± 9%, Δψ 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 H2 O2 formation, which can only partly be explained by its effect on Δψ. 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 QH2 /Q ratio ( C = −0.04) and Δψ ( 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. [ABSTRACT FROM AUTHOR]- Published
- 2006
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