小柯机器人

德国癌症研究中心Michaela Frye团队近期取得重要工作进展，他们研究揭示了线粒体RNA修饰影响了转移中的代谢可塑性。这一研究成果2022年6月29日在线发表于《自然》杂志上。

在这里，研究人员展示了两种NOP2/Sun RNA 甲基转移酶3 (NSUN3) 依赖性RNA修饰（5-甲基胞嘧啶 (m⁵C) 及其衍生物 5-甲酰基胞嘧啶 (f⁵C)），如何驱动线粒体mRNA的翻译为转移提供动力。线粒体氧化磷酸化复合物编码亚基的翻译取决于线粒体tRNA^Met中第34位 m⁵C的形成。m⁵C缺陷的人类口腔癌细胞表现出糖酵解水平升高和线粒体功能变化，这不影响细胞活力或体内原发性肿瘤生长；然而，代谢可塑性受到严重损害，因为线粒体 m⁵C 缺陷型肿瘤不能有效转移。研究人员发现，依赖CD36的非分裂、转移起始性肿瘤细胞需要线粒体m⁵C来激活侵袭和扩散。

此外，头颈癌患者中线粒体驱动的基因特征可预测转移和疾病进展。最后，研究人员证实，这种允许肿瘤细胞转移的代谢开关可以通过抑制体内线粒体mRNA翻译来进行药理学靶向。总之，他们的研究结果表明，位点特异性线粒体RNA修饰可能是对抗转移的治疗靶点。

据介绍，侵袭性和转移性癌症表现出增强的代谢可塑性，但其确切的潜在机制尚不清楚。

附：英文原文

Title: Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Author: Delaunay, Sylvain, Pascual, Gloria, Feng, Bohai, Klann, Kevin, Behm, Mikaela, Hotz-Wagenblatt, Agnes, Richter, Karsten, Zaoui, Karim, Herpel, Esther, Mnch, Christian, Dietmann, Sabine, Hess, Jochen, Benitah, Salvador Aznar, Frye, Michaela

Issue&Volume: 2022-06-29

Abstract: Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications—5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2,3,4)—drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m5C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.

DOI: 10.1038/s41586-022-04898-5

Source: https://www.nature.com/articles/s41586-022-04898-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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