Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Nutritional Sciences and Toxicology, UC Berkeley, Berkeley, CA, USA.
Nature. 2022 Mar;603(7902):736-742. doi: 10.1038/s41586-022-04488-5. Epub 2022 Mar 9.
Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 10 µm) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.
细胞通过将代谢过程分隔到细胞器中来显示复杂的细胞内组织，但这些结构在天然组织环境中的分辨率及其功能后果尚不清楚。在这里，我们使用增强型聚焦离子束扫描电子显微镜成像，在高分辨率（8nm 各向同性像素大小）下解析了完整肝组织（每个条件下 15 个部分或完整的肝细胞）中细胞器的三维结构组织。然后，我们进行了基于深度学习的自动图像分割和 3D 重建。我们还对瘦鼠和肥胖鼠肝组织中的亚细胞结构进行了比较分析，发现了实质性的改变，特别是在肝内质网（ER）中，其经历了大量的结构重组，其特征是 ER 片层的堆积明显紊乱和 ER 小管占主导地位。最后，我们通过监测细胞器组织的实验恢复对细胞和全身代谢的影响，证明了这些结构变化的功能重要性。我们的结论是，内质网架构的肝亚细胞组织具有高度动态性，与代谢状态整合在一起，对适应性动态平衡和组织健康至关重要。
