Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2)

Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2) is a flavin-linked enzyme located on the outer surface of the inner mitochondrial membrane. It serves as a critical component of the glycerol phosphate shuttle, which facilitates the transfer of reducing equivalents from cytosolic NADH into the mitochondrial electron transport chain to regenerate cytosolic NAD+ for glycolysis. Beyond its role in bioenergetics, GPD2 is a significant source of mitochondrial reactive oxygen species and acts as a calcium-responsive sensor in pancreatic beta-cells to regulate insulin secretion. In metabolic diseases like type 2 diabetes, GPD2 is a proposed target for the biguanide drug metformin, which inhibits the enzyme to reduce hepatic gluconeogenesis. In oncology, GPD2 is frequently overexpressed in various cancers, including prostate and thyroid cancer, where it supports the high metabolic demands and pro-oxidative phenotype of malignant cells. Consequently, GPD2 is being explored as a therapeutic target for both metabolic disorders and cancer through the development of small-molecule inhibitors.

Other names

mGPDHGPD-MGPDH-MmtGPDGlycerol-3-phosphate dehydrogenase 2Mitochondrial glycerophosphate dehydrogenase

Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase disrupts the glycerol phosphate shuttle, leading to an increased cytosolic NADH/NAD+ ratio and a decreased mitochondrial redox state, which suppresses hepatic gluconeogenesis and reduces reactive oxygen species production in cancer cells.