Figure 4.

Electron shuttles that intersect with the tricarboxylic acid (TCA) cycle or electron transport chain (ETC).A, in the glycerol 3-phosphate shuttle, the conversion of dihydroxyacetone phosphate into glycerol 3-phosphate by cytosolic glycerol 3-phosphate dehydrogenase 1 (GPD1) regenerates cytosolic NAD+ in the cytoplasm to support continued glycolysis. Glycerol 3-phosphate is subsequently converted back to dihydroxyacetone phosphate on the outer side of the inner mitochondrial membrane by mitochondrial glycerol 3-phosphate dehydrogenase 2 (GPD2), which is coupled with the conversion of FAD to FADH₂. FADH₂ donates electrons to ubiquinone (Q), reducing it to ubiquinol (QH₂) that passes its electrons to complex III of the ETC. B, in the malate–aspartate shuttle (left), the TCA cycle intermediate oxaloacetate (OAA) and glutamate undergo transamination by glutamic-oxaloacetic transaminase 2 (GOT2), producing alpha-ketoglutarate (αKG) and aspartate. Mitochondrial aspartate is exported to the cytoplasm by the mitochondrial transporter proteins SLC25A12 or SLC25A13, and this efflux is concomitant with import of glutamate and a proton. Cytosolic aspartate is consumed by the cytosolic transaminase GOT1, converting αKG to glutamate and producing OAA. Cytosolic OAA is converted to malate by malate dehydrogenase 1 (MDH1), which is coupled with oxidation of NADH to NAD+, supporting glycolysis by regenerating NAD⁺ required for GAPDH. MDH1-generated malate is then reimported into mitochondria via the transporter SLC25A11, which is coupled with efflux of mitochondrial αKG. MDH2 converts malate to OAA, thereby reducing NAD⁺ to NADH and completing the cycle. In the citrate–malate shuttle (right), the citrate–malate antiporter SLC25A1 exports citrate to the cytosol, where it undergoes energy-dependent cleavage by ATP-citrate lyase (ACL), liberating acetyl-CoA and OAA. Conversion of OAA to malate by MDH1 supports NADH oxidation to NAD⁺, and this malate is imported into mitochondria in exchange for citrate by SLC25A1. In the mitochondria, malate is oxidized to OAA by MDH2, completing the shuttling of NADH into the mitochondrion.