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Review
. 2016 Jun:38:102-109.
doi: 10.1016/j.gde.2016.05.003. Epub 2016 Jun 5.

Mitochondrial pyruvate carrier function and cancer metabolism

Adam J Rauckhorst  1 , Eric B Taylor  2
Affiliations
Review

Mitochondrial pyruvate carrier function and cancer metabolism

Adam J Rauckhorst et al. Curr Opin Genet Dev. 2016 Jun.

Abstract

Metabolic reprogramming in cancer supports the increased biosynthesis required for unchecked proliferation. Increased glucose utilization is a defining feature of many cancers that is accompanied by altered pyruvate partitioning and mitochondrial metabolism. Cancer cells also require mitochondrial tricarboxylic acid cycle activity and electron transport chain function for biosynthetic competency and proliferation. Recent evidence demonstrates that mitochondrial pyruvate carrier (MPC) function is abnormal in some cancers and that increasing MPC activity may decrease cancer proliferation. Here we examine recent findings on MPC function and cancer metabolism. Special emphasis is placed on the compartmentalization of pyruvate metabolism and the alternative routes of metabolism that maintain the cellular biosynthetic pools required for unrestrained proliferation in cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Glycolysis and the TCA cycle are linked by a common molecule, pyruvate, and the activity of the MPC, which conducts pyruvate across the mitochondrial inner membrane. Glycolytic and TCA cycle intermediates support biosynthetic pathways: Glycolysis provides carbon in the form of glucose 6-phosphate to the pentose phosphate pathway for reductive biosynthesis. Dihydroxyacetone supports phospholipid and triacylglycerol biosynthesis. 3-phosphoglycerate supports production of amino acids and ceramide. The TCA cycle generates citrate that supports cytoplasmic production of acetyl-CoA for de novo lipogenesis. Oxaloacetate may be transaminated to aspartate for amino acid biosyntheses.
Figure 2
Figure 2
Metabolic reprogramming alters pyruvate metabolism in some cancers: A) Dimeric PKM2 prevents the glycolytic production of pyruvate. Pyruvate is shunted away from mitochondrial metabolism by reduction to lactate. B) Citrate produced by the TCA cycle is converted to acetyl-CoA in the cytoplasm for de novo lipogenesis. Acetyl-CoA may also be generated directly from acetate by acetyl-CoA synthetase 2. C) In the absence of MPC activity in highly oxidative cancers glutaminolysis maintains TCA cycle intermediate pools. When MPC activity is decreased, reductive carboxylation of α-ketoglutarate supports citrate production for de novo lipogenesis. D) Some cancers rely on pyruvate carboxylase to produce oxaloacetate. Oxaloacetate may be transaminated to aspartate to support protein synthesis.
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