澳大利亚QEII医疗中心Aleksandra Filipovska团队近期取得重要工作进展，他们通过定量亚细胞重建揭示了脂质介导的细胞器间生物发生网络。相关研究成果2023年12月21日在线发表于《自然—细胞生物学》杂志上。

据介绍，细胞器的结构和功能相互依赖，但尚未得到系统的探索。

研究人员建立了过氧化物酶体、高尔基体和内质网基因的稳定敲除细胞系，在全基因组CRISPR敲除筛选中鉴定了线粒体生物发生应激的诱导物，表明过氧化物酶体、高尔基体和内质网代谢的缺陷破坏了线粒体的结构和功能。聚焦离子束扫描电子显微镜的定量全细胞器分析方法以前所未有的细节揭示了特定细胞器功能障碍加速多细胞器生物发生缺陷，损害线粒体形态并减少呼吸。

多组学分析显示，当细胞器生物发生受损时，会引发统一的蛋白质组反应和脂质和糖蛋白稳态的全局变化，并且由此产生的线粒体功能障碍可以通过醚-甘油磷脂代谢途径的前体来挽救。

总之，这项工作定义了细胞器之间的代谢和形态学相互作用，以及它们的扰动如何导致疾病。

附：英文原文

Title: Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network

Author: Lee, Richard G., Rudler, Danielle L., Raven, Samuel A., Peng, Liuyu, Chopin, Analle, Moh, Edward S. X., McCubbin, Tim, Siira, Stefan J., Fagan, Samuel V., DeBono, Nicholas J., Stentenbach, Maike, Browne, Jasmin, Rackham, Filip F., Li, Ji, Simpson, Kaylene J., Marcellin, Esteban, Packer, Nicolle H., Reid, Gavin E., Padman, Benjamin S., Rackham, Oliver, Filipovska, Aleksandra

Issue&Volume: 2023-12-21

Abstract: The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology and reduce respiration. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised, and that the resulting mitochondrial dysfunction can be rescued with precursors for ether-glycerophospholipid metabolic pathways. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease.

DOI: 10.1038/s41556-023-01297-4

Source: https://www.nature.com/articles/s41556-023-01297-4