The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization
The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization
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DOI：
10.1074/jbc.m112.435495
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发表时间：
2013-02-08
影响因子：
4.8
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Ward, Patrick S.;Lu, Chao;Thompson, Craig B.
胞质异柠檬酸脱氢酶1（IDH 1）及其线粒体同源物IDH 2中的单等位基因点突变可导致多种癌症中2-羟基戊二酸（2 HG）水平升高。在这里，我们报告说，从胞质IDH 1突变的细胞2 HG生产是依赖于保留野生型IDH 1等位基因的活性。相比之下，线粒体IDH 2突变的表达以独立于野生型线粒体IDH功能的方式导致稳健的2 HG产生。在Arg-172和Arg-140处的复发性IDH 2突变中，IDH 2 Arg-172突变一致地导致比IDH 2 Arg-140突变更大的2 HG积累，并且2 HG积累的程度与这些突变阻断细胞分化的能力相关。胞质IDH 1 Arg-132突变，尽管在结构上类似于线粒体IDH 2 Arg-172处的突变，但仅当共表达同等水平的野生型IDH 1时，才能够将胞内2 HG升高至相当的水平。与来自胞质IDH 1的2 HG产生受到来自野生型IDH 1的底物产生的限制一致，我们观察到当线粒体IDH通量转向胞质时，2 HG水平在携带内源性单等位基因IDH 1突变的癌细胞中增加。最后，表达的IDH 1构建工程定位到线粒体，而不是胞质溶胶导致更大的2 HG积累。这些数据表明，等位基因和亚细胞区室差异可以调节IDH突变在细胞中产生2 HG的潜力。2 HG升高的后果是剂量依赖性的，并且由IDH 1和IDH 2突变引起的不相等的2 HG积累可能是其在各种癌症中的不同预后和患病率的基础。
Monoallelic point mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) and its mitochondrial homolog IDH2 can lead to elevated levels of 2-hydroxyglutarate (2HG) in multiple cancers. Here we report that cellular 2HG production from cytosolic IDH1 mutation is dependent on the activity of a retained wild-type IDH1 allele. In contrast, expression of mitochondrial IDH2 mutations led to robust 2HG production in a manner independent of wild-type mitochondrial IDH function. Among the recurrent IDH2 mutations at Arg-172 and Arg-140, IDH2 Arg-172 mutations consistently led to greater 2HG accumulation than IDH2 Arg-140 mutations, and the degree of 2HG accumulation correlated with the ability of these mutations to block cellular differentiation. Cytosolic IDH1 Arg-132 mutations, although structurally analogous to mutations at mitochondrial IDH2 Arg-172, were only able to elevate intracellular 2HG to comparable levels when an equivalent level of wild-type IDH1 was co-expressed. Consistent with 2HG production from cytosolic IDH1 being limited by substrate production from wildtype IDH1, we observed 2HG levels to increase in cancer cells harboring an endogenous monoallelic IDH1 mutation when mitochondrial IDH flux was diverted to the cytosol. Finally, expression of an IDH1 construct engineered to localize to the mitochondria rather than the cytosol resulted in greater 2HG accumulation. These data demonstrate that allelic and subcellular compartment differences can regulate the potential for IDH mutations to produce 2HG in cells. The consequences of 2HG elevation are dose-dependent, and the non-equivalent 2HG accumulation resulting from IDH1 and IDH2 mutations may underlie their differential prognosis and prevalence in various cancers.