U.S. Department of Health and Human Services

Solving a Decades old Mystery Yields Insight into Metabolic Disease

After decades of investigation, a transport complex that carries the metabolite pyruvate from the cytoplasm into the mitochondria has been identified. Pyruvate is a key intermediate in carbohydrate, fat, and amino acid metabolism. It is usually produced in the cytoplasm, and then is transported into the mitochondria—the “powerhouses” of the cell—where it is metabolized further. How pyruvate gains entrance into the mitochondria has remained a mystery. Solving this mystery has important implications because altered metabolism underlies common diseases, such as type 2 diabetes and obesity, and, as shown in this study, a less common but devastating disease caused by impaired mitochondrial pyruvate metabolism. 
Using an elegant series of genetics, metabolomics, and other analyses, scientists have identified two related proteins, mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2), that form a complex that transports pyruvate from the cytoplasm into the mitochondria. The genes Mpc1 and Mpc2 were initially identified as part of an ongoing effort to characterize mitochondrial proteins that are conserved through evolution. Both yeast and fly mutants lacking the Mpc1 gene showed reduced pyruvate metabolism; under certain conditions this resulted in poor growth or lethality. Experiments in yeast suggested that the defect was due to diminished entry of pyruvate into mitochondria, thus implicating MPC1 as a pyruvate carrier. Further evidence of MPC1’s role in pyruvate transport was provided by studying a chemical, UK-5099, that has been used experimentally to block the activity of pyruvate transport into mitochondria since 1975—even though scientists had not known the exact target of its effects. When assessed in this study, UK-5099 was shown to be a potent inhibitor of MPC1-mediated pyruvate transport in yeast. Further studies in yeast designed to evaluate the interaction between MPC1 and MPC2 suggest that these proteins form a multimeric complex (more than one copy of each protein present) in the mitochondrial membrane. Building on the findings in yeast and flies, the researchers next examined whether MPC1 and MPC2 are involved in transport of pyruvate in mammals. In mouse cells in laboratory culture, turning off the Mpc1 or Mpc2 gene impaired pyruvate metabolism. In addition, genetics studies in humans showed that in three unrelated families, children with a devastating disease caused by impaired mitochondrial pyruvate metabolism had mutations in Mpc1. Thus, the findings suggest that MPC1 and MPC2 are also serving as pyruvate carriers in humans, and give insight into a serious genetic disease. 
The findings of this study solve a mystery that has perplexed scientists working in this area for many years. Moving forward, the identification of these pyruvate carrier proteins opens up new research directions that could be pursued for treating a variety of metabolic diseases. 
Bricker DK, Taylor EB, Schell JC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337: 96-100, 2012.