Nguyen Nicholas D, Yu Meifang, Reddy Vinit Y, Acevedo-Diaz Ariana C, Mesarick Enzo C, Abi Jaoude Joseph, Yuan Min, Asara John M, Taniguchi Cullen M
Department of Experimental Radiation Oncology, The University of Texas at MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Radiation Oncology, The University of Texas at MD Anderson Cancer Center, Houston, TX 77030, USA.
Metabolites. 2021 Sep 15;11(9):627. doi: 10.3390/metabo11090627.
Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
线粒体是动态细胞器，通过募集诸如线粒体融合蛋白2（Mfn2）和动力相关蛋白1（Drp1）等特殊蛋白质不断改变其形状。Mfn2诱导附近线粒体融合，而Drp1介导线粒体分裂。我们之前发现在多个模型系统中，线粒体融合的基因或药理学激活对胰腺导管腺癌（PDAC）具有肿瘤抑制作用。这些不同的线粒体融合诱导剂如何降低胰腺癌生长的机制仍不清楚。在此，我们对KPC细胞中诱导线粒体融合的三种独立方法进行了特征分析和代谢重编程比较：Mfn2过表达、Drp1基因编辑或来氟米特处理。我们通过强大的正交统计分析鉴定出显著改变的代谢物，发现线粒体融合始终会导致氨基酸代谢的改变。我们的无偏方法表明，所有这些诱导线粒体融合的方法都会产生相似的代谢扰动，为用其他药物进行代谢靶向提出了一条共同途径。
