Fig. 3.

Schematic presentations of the yeast mitochondrial respiratory chain and the NADH shuttle system. Mitochondrial NADH dehydrogenases (ND) oxidize NADH from both the cytosolic and mitochondrial pools to regenerate NAD⁺. The electrons acquired are then passed down the electron transport chain to the terminal acceptor oxygen (O₂). CR activates mitochondrial activity, which results in an increase in NAD⁺/NADH ratio. Since the mitochondrial inner membrane is impermeable to NAD⁺ and NADH, this increase in NAD⁺/NADH ratio is transmitted into the cytosolic/nuclear pools via the NADH shuttle system. The NADH shuttle system affects the NAD/NADH ratio indirectly by coupling the redox reaction of NAD⁺ and NADH with the redox reactions of permeable redox equivalents of NAD⁺ and NADH. In the example shown here, cytosolic malate dehydrogenase (Mdh2) couples the oxidation of NADH with the reduction of oxaloacetate (O). The resulting reduced product malate (M) enters the mitochondria via specific carriers and thereby shuttling redox equivalents into the mitochondrial matrix. In the mitochondrial matrix, mitochondrial Mdh1 catalyzes the generation of NADH from NAD⁺ and electrons carried by malate (M) are concurrently oxidized to oxaloacetate (O). Mitochondrial aspartate aminase (Aat1) then converts oxaloacetate to aspartate (A), which is subsequently transported to the cytosol via other carriers. Cytosolic Aat2 then regenerates oxaloacetate from aspartate, and another round of NADH shuttling is ready to resume. With the NADH shuttle system, alterations of the mitochondrial NAD⁺/NADH ratio resulted from the increase of mitochondrial respiration could be conveyed to the cytosolic/nuclear compartments.