小柯机器人

小分子抑制剂可有效抑制人线粒体DNA转录
2020-12-17 13:51

德国马克斯·普朗克衰老生物学研究所Nils-Gran Larsson和瑞典哥德堡大学Claes M. Gustafsson研究组合作,发现了人类线粒体DNA(mtDNA)转录的小分子抑制剂。该研究成果于2020年12月16日在线发表在国际学术期刊《自然》上。

研究人员发现了靶向人类线粒体RNA聚合酶(POLRMT)从而抑制线粒体转录(IMTs)的一线特异性抑制剂,POLRMT对于氧化磷酸化(OXPHOS)通路至关重要。在体外重组系统中IMT能有效抑制mtDNA转录,并在细胞系中产生剂量依赖性抑制mtDNA表达和OXPHOS的效果。为了验证其在细胞中的分子靶点,研究人员对诱变的细胞进行了外显子组测序,并在POLRMT中鉴定了引起IMT抗性的氨基酸取代簇。

研究人员解析了与IMT与 POLRMT结合的冷冻电镜(cryo-EM)结构,该结构进一步确定了POLRMT活性中心裂附近的变构结合位点。先前的报道证明了癌细胞的生长和对治疗有抗性癌症干细胞的持久性取决于OXPHOS,因此研究人员检测了IMT是否具有抗肿瘤作用。尽管IMT治疗在人癌细胞的异种移植物中诱导了强烈的抗肿瘤反应,但小鼠可以耐受四周的口服IMT治疗并且不会在正常组织中引起OXPHOS功能障碍或毒性。

综上所述,IMT提供了一种强大而特定的化学生物学工具来研究mtDNA表达在生理和疾病中的作用。

据了解,线粒体DNA表达的改变发生在衰老和一系列人类疾病中(例如:先天性代谢错误、神经变性和癌症)。

附:英文原文

Title: Small-molecule inhibitors of human mitochondrial DNA transcription

Author: Nina A. Bonekamp, Bradley Peter, Hauke S. Hillen, Andrea Felser, Tim Bergbrede, Axel Choidas, Moritz Horn, Anke Unger, Raffaella Di Lucrezia, Ilian Atanassov, Xinping Li, Uwe Koch, Sascha Menninger, Joanna Boros, Peter Habenberger, Patrick Giavalisco, Patrick Cramer, Martin S. Denzel, Peter Nussbaumer, Bert Klebl, Maria Falkenberg, Claes M. Gustafsson, Nils-Gran Larsson

Issue&Volume: 2020-12-16

Abstract: Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1,2,3,4,5,6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7,8,9,10,11,12,13,14,15,16,17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

DOI: 10.1038/s41586-020-03048-z

Source: https://www.nature.com/articles/s41586-020-03048-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0