Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Metabolite Profiling, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell Metab. 2019 Apr 2;29(4):856-870.e7. doi: 10.1016/j.cmet.2018.12.023. Epub 2019 Jan 24.
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 in vivo. 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 SLC16A11 that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity in vitro 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.
由 δ-5 和 δ-6 去饱和酶（D5D/D6D）催化的反应是高度不饱和脂肪酸（HUFA）合成的关键酶，可将 NADH 再生为 NAD。在这里，我们表明 D5D/D6D 提供了一种糖酵解 NAD 循环的机制，当细胞溶质 NAD/NADH 比率降低时，类似于乳酸发酵，可允许持续的糖酵解和细胞存活。尽管其幅度小于乳酸产生，但在体内有氧呼吸受损时，这种由去饱和酶介导的 NAD 循环是急性适应性的。值得注意的是，抑制 HUFA 合成或乳酸发酵都会增加另一种，突出了它们的相互依存性。与此一致的是，SLC16A11 中的一种 2 型糖尿病风险单倍型降低了丙酮酸转运（从而限制了乳酸的产生），从而增加了体外和人体内的 D5D/D6D 活性，证明了去饱和酶介导的 NAD 循环的慢性作用。这些发现强调了 D5D/D6D 活性的关键生物学作用，独立于其 HUFA 终产物，并扩展了当前糖酵解 NAD 再生的范例。
