苹果酸酶 2 将克雷布斯循环中间体延胡索酸与线粒体生物发生联系起来。
Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis.
机构信息
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai 20032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 20032, China.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
出版信息
Cell Metab. 2021 May 4;33(5):1027-1041.e8. doi: 10.1016/j.cmet.2021.03.003. Epub 2021 Mar 25.
Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate.
线粒体具有独立的基因组（mtDNA）和蛋白质合成机制，这些机制协同激活以产生线粒体。在这里，我们报告称，三羧酸循环中间体富马酸通过与苹果酸酶 2（ME2）结合，将代谢与线粒体生物发生联系起来。从机制上讲，富马酸与 ME2 结合具有两个互补的后果。首先，促进 ME2 二聚体的形成，从而激活脱氧尿苷 5'-三磷酸核苷水解酶（DUT）。DUT 促进胸苷的产生和 mtDNA 的增加。其次，富马酸诱导的 ME2 二聚体使 ME2 单体脱离与线粒体核糖体蛋白 L45 的结合，使其能够进行线粒体核糖体组装和 mtDNA 编码蛋白的产生。蛋白精氨酸甲基转移酶 1 对 ME2-富马酸结合位点的甲基化抑制富马酸信号，从而限制线粒体生物发生。值得注意的是，急性髓系白血病高度依赖线粒体功能，并且对富马酸-ME2 轴的靶向治疗敏感。因此，通过 ME2 可以在正常和恶性细胞中操纵线粒体生物发生，ME2 是一种意想不到的线粒体生物量产生的调节因子，它通过富马酸感知营养物质的可用性。
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