Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis
Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis
复制标题
DOI：
10.1016/j.celrep.2021.108873
复制
发表时间：
2021-03-16
期刊：
影响因子：
8.8
通讯作者：
Pellegrini, Luca
中科院分区：
文献类型：
--
作者：
Anastasia, Irene;Ilacqua, Nicolo;Pellegrini, Luca
细胞器之间的接触产生微结构域，在调节关键的细胞内活动和信号通路中发挥重要作用，但它们是否也调节系统功能仍然未知。在这里，我们报告了紧密包裹在线粒体（wrappER）周围的弯曲粗面内质网片建立的细胞器间接触的超微结构组织和动力学。为了阐明这种接触的体内功能，通过转录组学、蛋白质组学和脂质组学分析了富含wrappER相关线粒体的小鼠肝脏组分。 wrappER 的生化特征表明其在极低密度脂蛋白 (VLDL) 的生物发生中发挥作用。改变wrappER-线粒体接触会减少VLDL分泌并增加肝脂肪酸、脂滴和中性脂质含量。相反，Mttp（VLDL 生物发生的最上游调节因子）的急性肝脏特异性消融，重现了这种肝脏血脂异常表型，并促进了wrappER-线粒体接触的重塑。肝wrappER-线粒体接触参与VLDL生物学的发现表明细胞器间接触参与全身脂质稳态。
Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.