glycerolshuttle

The glycerol phosphate shuttle, often referred to as the glycerol shuttle, is a pathway that transfers reducing equivalents from cytosolic NADH into the mitochondrial electron transport chain. Its primary role is to regenerate cytosolic NAD+, allowing glycolysis to continue when oxygen is present.

Mechanism: In the cytosol, dihydroxyacetone phosphate (DHAP) is reduced to glycerol-3-phosphate by cytosolic glycerol-3-phosphate dehydrogenase (GPD1) using NADH, converting NADH to NAD+. Glycerol-3-phosphate then diffuses to the outer surface of the inner mitochondrial membrane, where mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) oxidizes it back to DHAP. In this step, electrons are transferred to flavin adenine dinucleotide (FAD) within GPD2, forming FADH2, which donates electrons to coenzyme Q in the electron transport chain.

Energetics: The electrons ultimately enter the respiratory chain as ubiquinol via FADH2, yielding about 1.5 ATP per cytosolic NADH. This is less efficient than the malate-aspartate shuttle, which can yield roughly 2.5 ATP per NADH.

Physiological role and distribution: The glycerol phosphate shuttle is particularly important in tissues with high glycolytic flux, such as skeletal muscle and certain adipose tissues. It provides a rapid means to regenerate cytosolic NAD+ and sustain glycolysis, albeit with lower overall ATP yield per NADH compared with other shuttles. The relative contribution of the glycerol phosphate shuttle varies by tissue and metabolic state, often coexisting with the malate-aspartate shuttle.