Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling

<h2>Summary</h2> The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD⁺ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD⁺ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD⁺/NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD⁺ recycling is acutely adaptive when aerobic respiration is impaired <i>in vivo</i>. Notably, inhibition of either HUFA synthesis or lactate fermentation increases the other, underscoring their interdependence. Consistent with this, a type 2 diabetes risk haplotype in <i>SLC16A11</i> that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity <i>in vitro</i> and in humans, demonstrating a chronic effect of desaturase-mediated NAD⁺ recycling. These findings highlight key biologic roles for D5D/D6D activity independent of their HUFA end products and expand the current paradigm of glycolytic NAD⁺ regeneration.