Mitochondrial glycerophosphate dehydrogenase (mGPDH) (mGPDH)

Mitochondrial glycerophosphate dehydrogenase (mGPDH) is a key enzyme located on the inner mitochondrial membrane that participates in the glycerol-3-phosphate shuttle, transferring reducing equivalents from the cytosol to the mitochondria [1, 2]. This process is vital for maintaining the cytosolic NAD+/NADH ratio, which in turn regulates the rate of hepatic gluconeogenesis by controlling the availability of substrates like lactate and glycerol [1, 3]. Inhibition of mGPDH leads to an altered redox state (increased cytosolic NADH), which prevents the conversion of lactate to pyruvate, effectively stalling the gluconeogenic pathway [1, 4]. This mechanism is the primary molecular target for Metformin, the most widely prescribed medication for Type 2 Diabetes Mellitus [1, 3]. By targeting this redox-dependent regulatory node, pharmacological agents can reduce excessive hepatic glucose production without the risk of hypoglycemia associated with other insulin-sensitizing therapies [3, 4]. References: [1] Madiraju AK, et al. Nature. 2014;510(7506):542-546. [2] UniProt KB - P43304 (GPD2_HUMAN). [3] LaMoia TE, Shulman GI. Endocr Rev. 2021;42(1):77-96. [4] StatPearls: Metformin.

Other names

Glycerol-3-phosphate dehydrogenase 2GPD2Mitochondrial glycerol-3-phosphate dehydrogenasemGPDHepatic gluconeogenesis redox-dependent regulation pathway

Inhibition of mGPDH leads to an increase in the cytosolic NADH/NAD+ ratio, which mass-action inhibits the conversion of lactate to pyruvate and glycerol-3-phosphate to dihydroxyacetone phosphate, thereby suppressing hepatic gluconeogenesis [1, 3].