Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3η in oncocytomas
Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3η in oncocytomas
复制标题
嗜酸细胞瘤中 14-3-3 eta 介导的线粒体生物发生的增强和乳酸脱氢酶的矛盾抑制
DOI：
10.1002/path.5090
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发表时间：
2018-07-01
影响因子：
7.3
通讯作者：
Zhang, Yazhuo
中科院分区：
文献类型：
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作者：
Feng, Jie;Zhang, Qi;Zhang, Yazhuo
嗜酸细胞瘤是良性垂体腺瘤的一个亚型，其特征是显著的线粒体增生。线粒体是肿瘤细胞中产生能量和产生生物合成代谢中间产物的关键细胞器，因此了解嗜酸细胞瘤中线粒体生物发生的机制及其对细胞代谢的影响至关重要。在这里，我们研究了手术切除的垂体嗜酸细胞瘤，使用多组学分析。全外显子组测序没有发现任何核突变，但确定了线粒体DNA的几个体细胞突变和功能失调的呼吸复合物I。代谢组学分析表明，个别线粒体内氧化磷酸化减少，糖酵解活性没有相互增加。有趣的是，我们发现细胞乳酸水平降低，乳酸脱氢酶A（LDHA）的表达减少，这有助于体外细胞模型中的线粒体生物合成。值得注意的是，缺氧反应信号通路在垂体嗜酸细胞瘤中没有上调，因此未能增强糖酵解。蛋白质组学分析表明，14-3-3 eta只在嗜酸细胞瘤中过表达，并且14-3-3 eta能够抑制糖酵解，导致在鱼藤酮存在下的线粒体生物合成。特别是，14-3-3 eta通过在复合物I功能障碍的情况下的直接相互作用抑制LDHA，突出了14-3-3 eta过表达和低效氧化磷酸化在嗜酸细胞瘤线粒体生物发生中的作用。这些发现加深了我们对嗜酸细胞瘤内发生的代谢变化的理解，并揭示了线粒体生物发生的机制，为肿瘤细胞的代谢适应提供了新的视角。(C)2018作者病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3 eta was exclusively overexpressed in oncocytomas, and that 14-3-3 eta was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3 eta inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3 eta overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. (C) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.