小柯机器人

英国威康桑格研究所Nicole Soranzo等研究人员合作发现，线粒体DNA变体调节N-甲酰甲硫氨酸、蛋白质稳定和人类晚期疾病的风险。2021年8月23日，《自然—医学》杂志在线发表了这一最新研究成果。

研究人员对16,220名健康捐赠者的5689个血源生物标志物与线粒体DNA（mtDNA）变体进行了无假设分析。结果显示，定义mtDNA单倍群Uk和H4的变体能够调节循环中N-甲酰甲硫氨酸（fMet）的水平，它能启动线粒体蛋白翻译。在人类细胞质杂交（cybrid）系中，fMet通过转录、翻译后修饰和N-egron途径的蛋白分解在多个层面上调节线粒体和细胞质蛋白，并消除了mtDNA单倍群之间的已知差异。在另外11,966人中，fMet水平对全因死亡率和几种常见的心血管疾病的疾病风险有贡献。

总之，这些发现表明，fMet通过对细胞蛋白稳态的多因素影响在常见的年龄相关疾病中起着关键作用。

据悉，mtDNA变异会影响人类晚期疾病的风险，但其原因却不甚明了。

附：英文原文

Title: Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases

Author: Cai, Na, Gomez-Duran, Aurora, Yonova-Doing, Ekaterina, Kundu, Kousik, Burgess, Annette I., Golder, Zoe J., Calabrese, Claudia, Bonder, Marc J., Camacho, Marta, Lawson, Rachael A., Li, Lixin, Williams-Gray, Caroline H., Di Angelantonio, Emanuele, Roberts, David J., Watkins, Nick A., Ouwehand, Willem H., Butterworth, Adam S., Stewart, Isobel D., Pietzner, Maik, Wareham, Nick J., Langenberg, Claudia, Danesh, John, Walter, Klaudia, Rothwell, Peter M., Howson, Joanna M. M., Stegle, Oliver, Chinnery, Patrick F., Soranzo, Nicole

Issue&Volume: 2021-08-23

Abstract: Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis. The association between certain mitochondrial DNA variants and increased risk of late-onset diseases in humans could be explained by a direct role of mitochondrial DNA in the regulation of cellular proteostasis.

DOI: 10.1038/s41591-021-01441-3

Source: https://www.nature.com/articles/s41591-021-01441-3

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex