To test whether long-chain
fatty acyl-CoA esters link
obesity with
type 2 diabetes through inhibition of the mitochondrial
adenine nucleotide translocator, we applied a system-biology approach, dual modular kinetic analysis, with mitochondrial membrane potential (Deltapsi) and the fraction of matrix
ATP as intermediates. We found that 5 mumol/l
palmitoyl-CoA inhibited
adenine nucleotide translocator, without direct effect on other components of oxidative phosphorylation. Indirect effects depended on how oxidative phosphorylation was regulated. When the electron donor and
phosphate acceptor were in excess, and the mitochondrial "work" flux was allowed to vary,
palmitoyl-CoA decreased phosphorylation flux by 38% and the fraction of
ATP in the medium by 39%. Deltapsi increased by 15 mV, and the fraction of matrix
ATP increased by 46%.
Palmitoyl-CoA had a stronger effect when the flux through the mitochondrial electron transfer chain was maintained constant: Deltapsi increased by 27 mV, and the fraction of matrix
ATP increased 2.6 times. When oxidative phosphorylation flux was kept constant by adjusting the rate using
hexokinase, Deltapsi and the fraction of
ATP were not affected.
Palmitoyl-CoA increased the extramitochondrial
AMP concentration significantly. The effects of
palmitoyl-CoA in our model system support the proposed mechanism linking
obesity and
type 2 diabetes through an effect on
adenine nucleotide translocator.