Mitochondrial pyruvate transport: a historical perspective and future research directions

Abstract

Pyruvate is the end-product of glycolysis, a major substrate for oxidative metabolism, and a branching point for glucose, lactate, fatty acid and amino acid synthesis. The mitochondrial enzymes that metabolize pyruvate are physically separated from cytosolic pyruvate pools and rely on a membrane transport system to shuttle pyruvate across the impermeable inner mitochondrial membrane (IMM). Despite long-standing acceptance that transport of pyruvate into the mitochondrial matrix by a carrier-mediated process is required for the bulk of its metabolism, it has taken almost 40 years to determine the molecular identity of an IMM pyruvate carrier. Our current understanding is that two proteins, mitochondrial pyruvate carriers MPC1 and MPC2, form a hetero-oligomeric complex in the IMM to facilitate pyruvate transport. This step is required for mitochondrial pyruvate oxidation and carboxylation – critical reactions in intermediary metabolism that are dysregulated in several common diseases. The identification of these transporter constituents opens the door to the identification of novel compounds that modulate MPC activity, with potential utility for treating diabetes, cardiovascular disease, cancer, neurodegenerative diseases, and other common causes of morbidity and mortality. The purpose of the present review is to detail the historical, current and future research investigations concerning mitochondrial pyruvate transport, and discuss the possible consequences of altered pyruvate transport in various metabolic tissues.

The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters

“…Mpc1 was shown to be down-regulated or absent in many tumours and its over-expression impaired tumour cell growth [49], which does not fit easily with our data implicating inhibition of the MPC in the anti-tumour effects of LND. However, although it is now widely accepted that Mpc1 and Mpc2 form a multimeric MPC complex [51], questions have been raised over whether these proteins might exert their effects on pyruvate metabolism rather than transport [52]. In this context, it may be significant that measurement of the isotope flux of [ 13 C] into citrate from [U- 13 C]-glucose and [U- 13 C]-glutamine shows the specific MPC inhibitor UK5099 to have a much more profound effect on the labelling pattern of citrate than does Mpc1 or Mpc2 knockdown [50].…”

Energy metabolism and inflammation in brain aging and Alzheimer’s disease

“…The end metabolite of glycolysis, pyruvate, enters mitochondria via the mitochondrial pyruvate carrier (MPC) [64, 65] (Fig. 3).…”

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…Another method to inhibit pyruvate flux into gluconeogenesis is to block pyruvate transport across the inner mitochondrial membrane into the mitochondrial matrix, where it generates oxaloacetate for use in glucose production 118 . A heteroligomeric complex of mitochondrial pyruvate carrier 1 (MPC1) and MPC2 is necessary and sufficient for this transport of pyruvate 119,120 .…”