线粒体酶 L-2-羟基戊二酸脱氢酶 (L2HGDH) 调节 L-2-羟基戊二酸 (L-2HG) 的丰度，L-2HG 是一种有效的信号代谢物，能够影响染色质结构、线粒体代谢和细胞命运决定。人类 L2hgdh 活性的丧失会诱导异位 L-2HG 积聚，导致神经发育缺陷、免疫细胞功能改变以及透明细胞肾细胞癌的生长加快。为了更好地了解这些疾病病理基础的分子机制，我们使用果蝇果蝇来研究 L2hgdh 的内源功能。我们的研究表明，虽然 L2hgdh 对于标准培养条件下的生长或生存不是必需的，但 L2hgdh 突变体对缺氧高度敏感，并在复氧阶段失效，严重破坏线粒体代谢。此外，我们发现果蝇肾脏系统（马氏小管；MT）是 L2hgdh 活性的关键位点，因为在 MT 内表达救援转基因的 L2hgdh 突变体能够在缺氧处理中存活下来并表现出正常水平的线粒体代谢物。我们还证明，即使在常氧条件下，L2hgdh 突变 MT 也会经历显着的代谢应激，并且对 Egfr 激活后的异常生长敏感。总体而言，我们的研究结果提出了一个模型，其中肾脏 L2hgdh 活性限制全身 L-2HG 积累，从而间接调节糖酵解和线粒体代谢之间的平衡，实现缺氧暴露的成功恢复，并确保肾组织完整性。版权所有 © 2024 作者）。由 Elsevier GmbH 出版。保留所有权利。

The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh. Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, L2hgdh mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system (Malpighian tubules; MTs) is a key site of L2hgdh activity, as L2hgdh mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, L2hgdh mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. Overall, our findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.