美国哈佛大学David T. Scadden研究团队取得最新进展。他们发现苹果酸酶2可将Krebs循环中间体延胡索酸与线粒体生物发生联系起来。2021年3月25日出版的《细胞-代谢》杂志发表了这一研究成果。

他们报告说，Krebs循环中间产物延胡索酸通过与苹果酸酶2（ME2）的结合将代谢与线粒体发生联系起来。从机制上讲，延胡索酸结合ME2具有两个互补的结果。首先，促进ME2二聚体的形成，从而激活脱氧尿苷5'-三磷酸核苷酸水解酶（DUT）。DUT促进胸苷的产生和线粒体基因组（mtDNA）的增加。其次，延胡索酸诱导的ME2二聚体消除了ME2单体与线粒体核糖体蛋白L45的结合，并将其释放出来用于线粒体组装和mtDNA编码的蛋白产生。蛋白质精氨酸甲基转移酶-1对ME2-延胡索酸结合位点的甲基化抑制了延胡索酸的信号传导，从而限制了线粒体发生。

值得注意的是，急性髓细胞性白血病高度依赖于线粒体功能，并且对延胡索酸-ME2轴的靶向敏感。因此，可以通过ME2在正常和恶性细胞中操纵线粒体发生，ME2是线粒体生物量产生的不可预料的调控因素，可通过延胡索酸感测营养物质的可用性。

据了解， mtDNA和蛋白质合成机制，可以协同激活线粒体的生成。

附：英文原文

Title: Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis

Author: Yi-Ping Wang, Azeem Sharda, Shuang-Nian Xu, Nick van Gastel, Cheuk Him Man, Una Choi, Wei Zhong Leong, Xi Li, David T. Scadden

Issue&Volume: 2021-03-25

Abstract: Mitochondria have an independent genome (mtDNA) and protein synthesis machinery thatcoordinately activate for mitochondrial generation. Here, we report that the Krebscycle intermediate fumarate links metabolism to mitobiogenesis through binding tomalic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences.First, promoting the formation of ME2 dimers, which activate deoxyuridine 5′-triphosphatenucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA.Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrialribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded proteinproduction. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemiais highly dependent on mitochondrial function and is sensitive to targeting of thefumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignantcells through ME2, an unanticipated governor of mitochondrial biomass production thatsenses nutrient availability through fumarate.

DOI: 10.1016/j.cmet.2021.03.003

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00110-8