The transport of pyruvate into the mitochondria plays an important role in glucose oxidation, lipogenesis, and gluconeogenesis. It is also important for the metabolism of some amino acids.
In previous studies, researchers find a specific mitochondrial pyruvate carrier (MPC) inhibitor, a-cyano-4-hydroxycinnamate. And UK5099, a more potent analog, inhibiting the MPC by specifically modifying a thiol group on the carrier.

In this article, we will introduce a potent inhibitor of mitochondrial respiration, GW604714X.

GW604714X inhibits mitochondrial respiration supported by pyruvate but not other substrates. Besides, it also a highly specific mitochondrial pyruvate carrier (MPC) inhibitor with a Ki <0.1 nM. This Ki value is substantially lower than the value of 5-10 nM for UK5099.

The number of binding sites for GW450863X is greatest for the heart (55-60 pmol per mg protein). It requires rapid transport of pyruvate into the mitochondria to fuel the citric acid cycle for the provision of large amounts of ATP required for heart contraction.
The kidney (40 pmol per mg protein) is another metabolically active tissue. And it requires mitochondrial pyruvate transport for both the provision of ATP and gluconeogenesis.

In the liver, mitochondrial pyruvate transport plays role in gluconeogenesis. Where pyruvate is converted to oxaloacetate by pyruvate carboxylase within the mitochondrial matrix.
What’s more, GW604714X also inhibits L-lactate transport by the plasma membrane monocarboxylate transporter (MCT1), but at concentrations more than 4 orders of magnitude greater than the MPC.

Inhibitor titrations of pyruvate-dependent respiration by heart mitochondria gave values for the concentration of inhibitor binding sites and their Ki (nM) of 56.0 nM and 0.057 nM for the GW604714X.
GW604714X inhibits the transport of 0.5 mM [14C]-l-lactate into rat red blood cells. And this compound at 10 μM reduces the initial rate of uptake to 30% of control values.

In conclusion, we find that GW604714X is a potential MPC inhibitor and is an optimized analog of UK5099.


[1]. John C W Hildyard, et al.Biochim Biophys Acta. Apr-May 2005;1707(2-3):221-30.