Htet Pyae Hein, Avezov Edward, Lauga Eric
Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom.
UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Elife. 2024 Dec 13;13:RP93518. doi: 10.7554/eLife.93518.
The endoplasmic reticulum (ER), the largest cellular compartment, harbours the machinery for the biogenesis of secretory proteins and lipids, calcium storage/mobilisation, and detoxification. It is shaped as layered membranous sheets interconnected with a network of tubules extending throughout the cell. Understanding the influence of the ER morphology dynamics on molecular transport may offer clues to rationalising neuro-pathologies caused by ER morphogen mutations. It remains unclear, however, how the ER facilitates its intra-luminal mobility and homogenises its content. It has been recently proposed that intra-luminal transport may be enabled by active contractions of ER tubules. To surmount the barriers to empirical studies of the minuscule spatial and temporal scales relevant to ER nanofluidics, here we exploit the principles of viscous fluid dynamics to generate a theoretical physical model emulating in silico the content motion in actively contracting nanoscopic tubular networks. The computational model reveals the luminal particle speeds, and their impact in facilitating active transport, of the active contractile behaviour of the different ER components along various time-space parameters. The results of the model indicate that reproducing transport with velocities similar to those reported experimentally in single-particle tracking would require unrealistically high values of tubule contraction site length and rate. Considering further nanofluidic scenarios, we show that width contractions of the ER's flat domains (perinuclear sheets) generate local flows with only a short-range effect on luminal transport. Only contractions of peripheral sheets can reproduce experimental measurements, provided they are able to contract fast enough.
内质网（ER）是细胞内最大的区室，拥有分泌蛋白和脂质生物合成、钙储存/动员以及解毒的机制。它呈层状膜片结构，与延伸至整个细胞的小管网络相互连接。了解内质网形态动力学对分子运输的影响，可能为解释由内质网形态发生基因突变引起的神经病理学提供线索。然而，内质网如何促进其腔内移动并使内容物均匀化仍不清楚。最近有人提出，腔内运输可能是由内质网小管的主动收缩实现的。为了克服与内质网纳米流体相关的微小空间和时间尺度的实证研究障碍，在此我们利用粘性流体动力学原理，生成一个理论物理模型，在计算机上模拟主动收缩的纳米管状网络中的内容物运动。该计算模型揭示了不同内质网组分的主动收缩行为在各种时空参数下的腔内粒子速度及其对促进主动运输的影响。模型结果表明，要以与单粒子追踪实验报道的速度相似的速度再现运输，需要不切实际的高值的小管收缩位点长度和速率。考虑进一步的纳米流体情况，我们表明内质网扁平区域（核周片层）的宽度收缩仅对腔内运输产生短程效应的局部流动。只有外周片层的收缩才能再现实验测量结果，前提是它们能够足够快地收缩。
