Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

Abstract

Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC 50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.AMPK | pioglitazone | rosiglitazone | MSDC-0160 | XF PMP

Inhibition of Mitochondrial Pyruvate Transport by Zaprinast Causes Massive Accumulation of Aspartate at the Expense of Glutamate in the Retina

“…In this study we showed that MPC can also be inhibited by Zaprinast. Inhibition or knockdown of MPC prevents pyruvate-dependent acetyl-CoA formation and O 2 consumption (5,6,42) and decreases the lactate/pyruvate ratio (43). Our study shows that Zaprinast and UK5099 not only block pyruvate-dependent mitochondrial O 2 consumption and citrate synthesis in brain mitochondria but also cause increases in pyruvate and aspartate and decrease in glutamate in brain mitochondria and the retina.…”

De novo acetate production is coupled to central carbon metabolism in mammals

“…1d). We thus tested whether the pyruvate carrier inhibitor (UK5099) 23,24 that perturbs entry of pyruvate into the mitochondria would affect acetate generation. As expected, the 13 C labelled Ac-CoA, Ac-carnitine (reversibly converted from Ac-CoA) and citrate (the first intermediate in the TCA cycle) were decreased by UK5099 treatment ( Supplementary Figs.…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…While their chronic effects are mediated by PPAR-␥ (411), more direct acute effects on mitochondrial bioenergetics have been proposed. Glucose-stimulated respiration of INS-1 832/13 cells and rat islets was inhibited by pioglitazone (278), and specific mechanisms that have been proposed include inhibition of complex I (73,167) and an acute inhibition of the mitochondrial pyruvate transporter (125,342). Each mechanism would have the effect of restricting metabolism and thus indirectly activating AMPK.…”