How Cells Choose To Create Energy

To supply their energy needs, cells typically choose between utilizing glucose in the cytoplasm (aerobic glycolysis and lactic acid fermentation) or "burning" pyruvate in the mitochondria (mitochondrial carbohydrate oxidation). Although this is arguably the most fundamental metabolic decision that cells must make, prior to 2012 it was not clear how cells import pyruvate into mitochondria to fuel ATP production. That year, Rutter, Thummel and colleagues identified the heterodimeric MPC1/MPC2 complex as the mitochondrial pyruvate carrier. Their paper also identified and explained the severe metabolic defects found in families with mpc1 gene mutations. Rutter and collaborators have subsequently shown that the choice of whether or not to import pyruvate has far-reaching medical implications because stem cells and most cancer cells are glycolytic (the "Warburg Effect"). They showed that this is often because cells down-regulate MPC expression, and that MPC re-expression reverses the Warburg Effect, impedes tumor growth, and drives cell differentiation. These discoveries have revolutionized our understanding of the role of metabolic decisions in determining cell state and fate.