圣安东尼奥德克萨斯大学医学院健康科学中心的研究人员发现，有证据表明，新陈代谢(细胞中能源生产）中断与普遍的，往往也是致命类型的淋巴瘤相关。这一发现发表在《Nature Communications》杂志上。
“新陈代谢和癌症之间有关联”这个论题已经被提出或推断了很长一段时间，但鲜有直接关联证据证明代谢酶中基因突变。医学博士Ricardo 说。
“我们发现代谢失衡可致癌，”Aguiar博士说。研究团队成员包括来自健康科学中心医学和生物化学部门的成员，调查人员来自达拉斯德克萨斯大学西南医学中心和一组奥地利的合作者，他们发现编码D2-羟戊二酸脱氢酶(D2HGDH)的基因在一种癌症中发生突变，称为弥漫型巨型B细胞淋巴瘤。变异的淋巴瘤细胞显示缺乏一种称为α酮戊二酸的代谢物(α-KG)，该产物是维持细胞稳定与健康所必须的。
“当α-酮戊二酸处于异常低的水平时，另一种称为加双氧酶的酶也不会进行正常工作，从而引起大量其他连锁事件的发生”Aguiar博士说。他表示，α-酮戊二酸最近被确认是细胞老化和干细胞维护的关键调节器。“因此，我们研究结果的影响是广泛的，而不仅限于肿瘤生物学。”他说。
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D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2
.An-Ping Lin, Saman Abbas, Sang-Woo Kim, Manoela Ortega, Hakim Bouamar, Yissela Escobedo, Prakash Varadarajan, Yuejuan Qin, Jessica Sudderth, Eduard Schulz, Alexander Deutsch, Sumitra Mohan, Peter Ulz, Peter Neumeister, Dinesh Rakheja, Xiaoli Gao, Andrew Hinck, Susan T. Weintraub, Ralph J. DeBerardinis, Heinz Sill et al.
Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2‐HG into α‐KG, mediated by D2‐hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, wheras ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.