L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule may have physiologic roles that extend beyond its association with cancer as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite being highly expressed in the kidney, L2HGDH's role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh KO kidneys have no demonstrable histologic abnormalities. However, GC/MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-¹³C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction if L-2HG levels. Collectively, our studies provide new insight into the physiologic role for L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.

中文翻译：

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L-2-羟基戊二酸脱氢酶在肾脏中的目的学作用。


L-2-羟基戊二酸 (L-2HG) 是一种在肾肿瘤中含量升高的致癌代谢物。然而，该分子的生理作用可能超出其与癌症的关联范围，因为 L-2HG 水平因缺氧和果蝇幼虫发育过程而升高。已知 L-2HG 由 L-2HG 脱氢酶 (L2HGDH) 代谢，L2HGDH 的缺失会导致 L-2HG 水平升高。尽管 L2HGDH 在肾脏中高表达，但其在肾脏代谢中的作用尚未被探索。在此，我们利用新型 CRISPR/Cas9 小鼠敲除模型报告我们的发现，特别关注 L2HGDH 在肾脏中的作用。组织学上， L2hgdh KO肾脏没有明显的组织学异常。然而，GC/MS 代谢组学显示多种组织中 TCA 循环中间体琥珀酸的水平显着降低。 [U- ¹³ C]葡萄糖的同位素标记研究表明，肾癌细胞中 L2HGDH 的恢复（降低了 L-2HG）导致标记与 TCA 循环中间体的结合增强。随后的生化研究表明，L-2HG 可以抑制 TCA 循环酶 α-酮戊二酸脱氢酶。对肾肿瘤 mRNA 表达数据的生物信息分析表明，L2HGDH 与编码 TCA 循环酶的基因以及编码转录因子 PGC-1α 的基因共表达，PGC-1α 已知调节线粒体代谢。肾肿瘤细胞中 PGC-1α 的恢复导致 L2HGDH 表达增加，同时 L-2HG 水平降低。总的来说，我们的研究为 L2HGDH 的生理作用以及疾病状态下促进 L-2HG 积累的机制提供了新的见解。