Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.
Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.
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DOI：
10.1038/ncomms9784
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发表时间：
2015-11-02
影响因子：
16.6
通讯作者：
Tennant DA
中科院分区：
文献类型：
--
作者：
Lussey-Lepoutre C;Hollinshead KE;Ludwig C;Menara M;Morin A;Castro-Vega LJ;Parker SJ;Janin M;Martinelli C;Ottolenghi C;Metallo C;Gimenez-Roqueplo AP;Favier J;Tennant DA
三羧酸（TCA）循环是一个中心代谢途径，负责提供氧化磷酸化的还原电位和细胞生长、修复和增殖的合成代谢底物。因此，它被认为是细胞增殖和组织稳态所必需的。然而，自从最初报道副神经节瘤（PGL）中TCA循环酶复合物琥珀酸脱氢酶（SDH）失活突变以来，人们已经清楚地认识到，一些细胞和组织不仅能够在TCA循环被截断的情况下存活，而且还能够支持肿瘤中观察到的增殖性表型。在这里，我们表明SDH活性的丧失导致非必需氨基酸代谢的变化。特别是，我们证明了丙酮酸羧化酶是必要的重新供应耗尽的天冬氨酸池在sdh缺陷细胞。我们的研究结果表明，SDH的缺失降低了细胞的代谢可塑性，这表明脆弱性可以靶向治疗。
The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.