Liver mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH)

Liver mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is a flavin-dependent oxidoreductase located at the inner mitochondrial membrane, catalyzing the irreversible oxidation of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP) as part of the mitochondrial glycerophosphate shuttle. This shuttle system is critical for transferring reducing equivalents from the cytosol to the mitochondrial respiratory chain, thus linking glycolytic and lipid metabolic pathways with oxidative phosphorylation. In the liver, mGPDH acts as a key regulator of triglyceride synthesis and prevents hepatic steatosis; its deficiency promotes lipid accumulation, endoplasmic reticulum stress, and is implicated as a pathogenic factor in nonalcoholic fatty liver disease (NAFLD). The enzyme is regulated at multiple levels, including transcriptional activation and membrane localization, and relies on interaction with phospholipids and cofactors for activity. Structural studies reveal the enzyme operates as a dimer, has distinct membrane-interacting and FAD-binding domains, and shuttles electrons to ubiquinone in the respiratory chain. Currently, mGPDH is regarded as a possible therapeutic target for metabolic liver diseases due to its central role in nutrient metabolism and homeostasis.

Other names

Mitochondrial glycerol-3-phosphate dehydrogenaseG3PDH (mitochondrial form)GPD2 (gene symbol for human enzyme)

Competitive inhibition at the substrate-binding site. Interference with electron transfer to ubiquinone (Coenzyme Q). Inhibition leads to accumulation of glycerol-3-phosphate, impaired shuttle activity, and altered lipid metabolism.