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Review
. 2015 Mar 15;466(3):443-54.
doi: 10.1042/BJ20141171.

Mitochondrial pyruvate transport: a historical perspective and future research directions

Kyle S McCommis  1 , Brian N Finck  1
Affiliations
Review

Mitochondrial pyruvate transport: a historical perspective and future research directions

Kyle S McCommis et al. Biochem J. .

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.

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Figures

Figure 1
Figure 1. Pyruvate metabolic pathways
Pyruvate can be formed in the cytosol by glycolysis, or conversion from alanine by ALT, from lactate by LDH-B or from malate by malic enzyme (ME). Pyruvate crosses the outer mitochondrial membrane (OMM) probably via the VDAC into the intermembrane space (IMS). Pyruvate is then transported across the IMM by the MPC. It has also been suggested that the MPC transports ketone bodies across the IMM. In the mitochondrial matrix, pyruvate can be either oxidized into acetyl-CoA by PDH or carboxylated to oxaloacetate (OAA) by PC. Although pyruvate oxidation is important for the production of reducing equivalents for ATP synthesis, citrate formed in the TCA cycle can also be exported to the cytosol, converted to acetyl-CoA, and used to produce new fatty acids, cholesterol or acetylcholine. OAA produced by PC can be exported to the cytosol and converted to phosphoenolpyruvate (PEP), which can then be used to form glucose in gluconeogenic tissues such as the liver, kidney and intestine. Last, both mitochondrial energy produced from pyruvate oxidation and anaplerotic intermediates produced by pyruvate carboxylation play a role in the stimulation of insulin secretion in pancreatic β-cells by inhibiting K+ATP channels, causing depolarization of the plasma membrane, and Ca2+ influx through Ca2+V channels, and allowing insulin secretory vesicle fusion and insulin release.
Figure 2
Figure 2. Predicted molecular structure of MPC proteins
(A) An alignment of human MPC1 and MPC2 proteins is shown. Sequence conservation is colour-coded and predicted transmembrane domains are in shaded boxes. (B) A schematic representation of the predicted transmembrane topology of monomeric MPC proteins is shown and compared with the canonical SLC25 family proteins. MPC proteins, which are predicted to contain two or three transmembrane helices compared with six in SLC25 family proteins, are predicted to adopt opposing topological orientations and are also known to form hetero-oligomeric complexes. However, the stoichiometry and structure of these higher-order aggregates are not known.
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