甘油酸三磷酸穿梭系统（G3PS）是一种重要的NADH穿梭系统，它在细胞质内再生还原当量并在线粒体产生能量。在这里，我们证明G3PS在肾癌细胞中被解耦，在这种细胞中，细胞质反应的速度约为线粒体反应的4.5倍。高通量通过细胞质甘油酸-3-磷酸脱氢酶（GPD）是维持氧化还原平衡和支持脂质合成所必需的。有趣的是，通过敲低线粒体GPD（GPD2）抑制G3PS对线粒体呼吸没有影响。相反，GPD2缺失上调转录水平的细胞质GPD，并通过增加甘油酸-3-磷酸供应促进癌细胞增殖。GPD2敲低肿瘤的增殖优势可以通过药理抑制脂质合成来消除。综上所述，我们的结果表明，G3PS不需要作为完整的NADH穿梭系统运行，而是被截短以支持肾癌中的复杂脂质合成。版权所有 ©2023 Elsevier Inc.。

The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is ∼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.Copyright © 2023 Elsevier Inc. All rights reserved.