Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

中文翻译：

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Aldh1l2 敲除小鼠代谢组学将线粒体叶酸酶的丧失与罕见人类疾病中观察到的脂质代谢失调联系起来

线粒体叶酸酶 ALDH1L2（醛脱氢酶 1 家族成员 L2）将 10-甲酰基四氢叶酸转化为四氢叶酸和 CO2，同时产生 NADPH。我们最近报道了由于复合杂合突变导致的酶缺乏与男性患者的神经鱼鳞病综合征有关。在这里，我们解决了 ALDH1L2 在细胞代谢中的作用，并强调了该酶调节脂质氧化的机制。我们生成了 Aldh1l2 敲除 (KO) 小鼠模型，表征了其表型、组织组织学和减少的叶酸池水平，并应用非靶向代谢组学来确定由酶损失引起的肝脏、胰腺和血浆的代谢变化。我们还使用 NanoString Mouse Inflammation V2 Code Set 来分析炎症基因表达并评估 ALDH1L2 在炎症通路调节中的作用。雄性和雌性 Aldh1l2 KO 小鼠都是有活力的，并且没有表现出明显的表型。然而，H&E 和油红 O 染色揭示了 Aldh1l2-/- 雄性小鼠肝脏中央静脉和门静脉三联体之间脂质囊泡的积累，表明脂质代谢异常。代谢组学分析显示，这些小鼠肝脏和血浆中的代谢型发生了巨大变化，这表明脂肪酸远离 β-氧化。具体而言，血浆酰基肉碱和酰基甘氨酸结合物的急剧增加表明肝脏中的 β-氧化受损。我们的代谢组学数据进一步表明，从机制上讲，ALDH1L2 对脂质代谢的调节通过以下步骤与辅酶 A 的生物合成相关联。ALDH1L2 能够在线粒体中产生足够的 NADPH，以维持高水平的谷胱甘肽，而谷胱甘肽反过来又是支持高水平的半胱氨酸（辅酶 A 前体）所必需的。作为最终结果，由于 ALDH1L2 丢失导致脂质代谢失调导致线粒体中的 ATP 水平降低。ALDH1L2 功能对于 CoA 依赖性途径很重要，包括 β-氧化、TCA 循环和胆汁酸生物合成。ALDH1L2 在脂质代谢中的作用解释了为什么这种酶的丧失与神经皮肤疾病有关。在更广泛的范围内，我们的研究将叶酸代谢与细胞内脂质稳态和能量平衡的调节联系起来。