Mitochondrial glycerol-3-phosphate dehydrogenase and Mitochondrial complex I (NADH:ubiquinone oxidoreductase) (GPD2 and NDUFS1/Complex I)

Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH, GPD2) is an inner mitochondrial membrane–bound flavoprotein that catalyzes the oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate, transferring electrons from FADH2 to ubiquinone and thus into the electron transport chain. It is a key component of the glycerol phosphate shuttle, linking glycolytic NADH production with mitochondrial respiration and contributing to cellular redox balance, fatty acid metabolism, and thermogenic regulation, particularly in brown adipose tissue. Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is the largest enzyme complex of the mitochondrial respiratory chain. It catalyzes the transfer of electrons from NADH to ubiquinone (CoQ10), coupled to the pumping of protons across the inner mitochondrial membrane, which is essential for driving ATP synthesis via oxidative phosphorylation. Complex I consists of multiple subunits organized into a large L-shaped structure with modular domains for electron transfer and proton translocation. Dysfunction or inhibition of complex I is implicated in a range of metabolic, neurodegenerative, and cardiovascular diseases. Both enzymes play vital—but distinct—roles in mitochondrial metabolism, with mGPDH providing electrons via FADH2 to the respiratory chain and complex I providing electrons from NADH, converging at ubiquinone as the electron acceptor.

Other names

mGPDHGPD2sn-glycerol-3-phosphate dehydrogenase (mitochondrial)glycerolphosphate dehydrogenase 2NADH:ubiquinone oxidoreductaseNADH dehydrogenase (ubiquinone)respiratory complex I

mGPDH inhibitors: Block transfer of electrons from glycerol-3-phosphate to electron transport chain, disrupting NAD+/NADH balance and glycolytic flux. Complex I inhibitors: Prevent electron transfer from NADH to ubiquinone, disrupt proton gradient, impairing ATP production and promoting cell death in susceptible cells.