Glycerol-3-phosphate shuttle (GPD1 + GPD2)

The glycerol-3-phosphate (glycerophosphate) shuttle is the second mechanism, alongside the malate-aspartate shuttle, for delivering cytosolic reducing equivalents to the mitochondrial respiratory chain — and the dominant one in tissues such as brown adipose tissue, skeletal muscle and pancreatic beta-cells. Unlike the malate-aspartate shuttle it is unidirectional and feeds electrons directly into the ubiquinone pool rather than to Complex I, so it yields fewer ATP per cytosolic NADH but operates rapidly. In the cytosol, the NAD-linked glycerol-3-phosphate dehydrogenase GPD1 reduces dihydroxyacetone phosphate (DHAP) to sn-glycerol-3-phosphate, oxidising a cytosolic NADH to NAD+. The glycerol-3-phosphate then diffuses to the outer face of the inner mitochondrial membrane, where the FAD-dependent glycerol-3-phosphate dehydrogenase GPD2 (mGPDH) re-oxidises it back to DHAP and passes the two electrons through its FAD cofactor to ubiquinone, reducing it to ubiquinol; the DHAP returns to the cytosol to complete the cycle. Because GPD2 faces the intermembrane space, no metabolite crosses the inner membrane. GPD1 also supplies glycerol-3-phosphate for glycerolipid/triacylglycerol synthesis; loss-of-function of GPD1 causes transient infantile hypertriglyceridemia, and the shuttle is important in beta-cell glucose-stimulated insulin secretion.