Haigis lab re-evaluated a textbook NADH shuttle and found it is uncoupled in cancer

Graphical Abstract of process


To sustain high rates of glycolysis, rapidly dividing cancer cells rely on several mechanisms to regenerate reducing equivalents (in the form of NAD+) including mitochondrial NADH shuttles. The glycerol-3-phosphate shuttle is one of the two major NADH shuttles, along with the malate-aspartate shuttle. It serves as a metabolic hub connecting glycolysis, oxidative phosphorylation and lipid synthesis. However, the role of the glycerol-3-phosphate shuttle in cancer remains largely unexplored.

In this work, Yao et al. analyzed the expression of cytosolic and mitochondrial enzymes of the glycerol-3-phosphate shuttle using human TCGA datasets and found that the shuttle is uncoupled in a subset of cancers, including kidney cancer. They devised a new strategy to measure cytosolic versus mitochondrial reaction rate of this shuttle by using stable isotope-based metabolic flux analysis. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) supported the regeneration of NAD+ and complex lipid synthesis. Inhibition of mitochondrial GPD2 promoted cancer cell proliferation and sensitized them to lipid synthesis inhibitors. These results reveal that the glycerol-3-phosphate shuttle may not be required to function as an intact NADH shuttle system in cancer, but rather functions as a critical orchestrator of lipid synthesis. This work is in collaboration with Tony Hui from Harvard T.H. Chan School of Public Health and Arlene Sharpe from Department of Immunology.

Read the full paper here.