A Drosophila model of combined D-2- and L-2-hydroxyglutaric aciduria reveals a mechanism linking mitochondrial citrate export with oncometabolite accumulation.
A Drosophila model of combined D-2- and L-2-hydroxyglutaric aciduria reveals a mechanism linking mitochondrial citrate export with oncometabolite accumulation.
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DOI：
10.1242/dmm.035337
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发表时间：
2018-09-21
影响因子：
4.3
通讯作者：
Tennessen JM
中科院分区：
文献类型：
--
作者：
Li H;Hurlburt AJ;Tennessen JM
2-羟基戊二酸(2HG)的对映体是新陈代谢、染色质修饰和细胞命运决定的强有力的调节剂。虽然这些化合物与肿瘤代谢有关，通常被称为肿瘤代谢物，但D-和L-2HG也是由健康细胞合成的，可能具有内源性功能。在体内控制2HG代谢的代谢机制还知之甚少。细胞如何调节2HG水平的一个线索来自一种被称为混合性D-和L-2HG酸尿(D-/L-2HGA)的先天代谢错误，它导致D-和L-2HG积聚增加。由于这种疾病是由线粒体柠檬酸转运体(CIC)的突变引起的，因此柠檬酸必须以某种方式控制健康细胞中的2HG代谢。然而，柠檬酸盐和2HG之间的联系机制仍不清楚。在这里，我们使用果蝇黑腹果蝇来阐明柠檬酸运输和L-2HG积累之间的代谢联系。我们的研究表明，果蝇基因scheggia(SEA)编码果蝇CIC同源基因，抑制糖酵解通量，限制L-2HG的积累。此外，我们还发现，SEA突变体由于乳酸产量的增加而积累了过量的L-2HG，这可能是通过干扰L-2HG脱氢酶的活性来抑制L-2HG的降解。这一意想不到的结果表明，柠檬酸间接调节L-2HG的稳定性，并揭示了协调L-2HG代谢与糖酵解和三元酸循环的反馈机制。最后，我们的研究还提出了预防CIC缺乏症患者L-2HG蓄积的潜在策略。。摘要：这项研究揭示了线粒体柠檬酸输出与代谢产物L-2-羟基戊二酸积累有关的机制，提示有可能治疗D-2-和L-2-羟基戊二酸尿症，这是一种罕见的先天性代谢错误。
The enantiomers of 2-hydroxyglutarate (2HG) are potent regulators of metabolism, chromatin modifications and cell fate decisions. Although these compounds are associated with tumor metabolism and commonly referred to as oncometabolites, both D- and L-2HG are also synthesized by healthy cells and likely serve endogenous functions. The metabolic mechanisms that control 2HG metabolism in vivo are poorly understood. One clue towards how cells regulate 2HG levels has emerged from an inborn error of metabolism known as combined D- and L-2HG aciduria (D-/L-2HGA), which results in elevated D- and L-2HG accumulation. Because this disorder is caused by mutations in the mitochondrial citrate transporter (CIC), citrate must somehow govern 2HG metabolism in healthy cells. The mechanism linking citrate and 2HG, however, remains unknown. Here, we use the fruit fly Drosophila melanogaster to elucidate a metabolic link between citrate transport and L-2HG accumulation. Our study reveals that the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, dampens glycolytic flux and restricts L-2HG accumulation. Moreover, we find that sea mutants accumulate excess L-2HG owing to elevated lactate production, which inhibits L-2HG degradation by interfering with L-2HG dehydrogenase activity. This unexpected result demonstrates that citrate indirectly regulates L-2HG stability and reveals a feedback mechanism that coordinates L-2HG metabolism with glycolysis and the tricarboxylic acid cycle. Finally, our study also suggests a potential strategy for preventing L-2HG accumulation in human patients with CIC deficiency. . Summary: This study reveals a mechanism that links export of mitochondrial citrate to accumulation of the oncometabolite L-2-hydroxyglutarate, suggesting a potential treatment for individuals with combined D-2- and L-2-hydroxyglutaric aciduria, a rare inborn error of metabolism.
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DOI：
10.1073/pnas.1614102114
发表时间：
2017-02-07
影响因子：
11.1
作者：
Li, Hongde;Chawla, Geetanjali;Tennessen, Jason M.
通讯作者：
Tennessen, Jason M.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
8.4
作者：
Jiang L;Boufersaoui A;Yang C;Ko B;Rakheja D;Guevara G;Hu Z;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
7.4
作者：
Lommen, Arjen
通讯作者：
Lommen, Arjen
缺氧介导的 L-2-羟基戊二酸增加可协调对还原应激的代谢反应。
影响因子：
29
作者：
Oldham WM;Clish CB;Yang Y;Loscalzo J
通讯作者：
Loscalzo J