Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) (mGPDH)

Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), encoded by the GPD2 gene, is an enzyme located on the outer surface of the inner mitochondrial membrane (UniProt P43304). It is a key component of the glycerol phosphate shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain, thereby maintaining the cytosolic NAD+/NADH ratio (Orr et al., 2014, PubMed 24711448). By converting glycerol-3-phosphate to dihydroxyacetone phosphate and transferring electrons to ubiquinone via FAD, mGPDH links glycolysis and fatty acid metabolism to oxidative phosphorylation. In the context of disease, mGPDH is a major target for treating type 2 diabetes; its inhibition by metformin is proposed to increase the cytosolic NADH/NAD+ ratio, which suppresses hepatic gluconeogenesis from lactate (Madiraju et al., 2014, PubMed 24847880). Furthermore, mGPDH is overexpressed in several malignancies, including prostate and thyroid cancers, where it supports metabolic reprogramming and redox balance necessary for tumor growth (Langston et al., 2019, PubMed 30718877). Experimental small-molecule inhibitors like iGP-1 and iGP-5 are currently used to investigate its role as a therapeutic target for obesity and cancer.

Other names

Glycerol-3-phosphate dehydrogenase 2GPD2GPD-MMitochondrial glycerophosphate dehydrogenase

Inhibition of mGPDH activity leads to an increase in the cytosolic NADH/NAD+ ratio, which suppresses the conversion of lactate to pyruvate by lactate dehydrogenase, thereby inhibiting hepatic gluconeogenesis (Madiraju et al., 2014, PubMed 24847880).