Donahue Ekf, Hepowit N L, Keuchel B, Mulligan A G, Johnson D J, Ellisman M, Arrojo E Drigo R, MacGurn J, Burkewitz K
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA.
National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA.
bioRxiv. 2024 Aug 8:2024.08.07.607085. doi: 10.1101/2024.08.07.607085.
The endoplasmic reticulum (ER) comprises an array of structurally distinct subdomains, each with characteristic functions. While altered ER-associated processes are linked to age-onset pathogenesis, whether shifts in ER morphology underlie these functional changes is unclear. We report that ER remodeling is a conserved feature of the aging process in models ranging from yeast to and mammals. Focusing on as an exemplar of metazoan aging, we find that as animals age, ER mass declines in virtually all tissues and ER morphology shifts from rough sheets to tubular ER. The accompanying large-scale shifts in proteomic composition correspond to the ER turning from protein synthesis to lipid metabolism. To drive this substantial remodeling, ER-phagy is activated early in adulthood, promoting turnover of rough ER in response to rises in luminal protein-folding burden and reduced global protein synthesis. Surprisingly, ER remodeling is a pro-active and protective response during aging, as ER-phagy impairment limits lifespan in yeast and diverse lifespan-extending paradigms promote profound remodeling of ER morphology even in young animals. Altogether our results reveal ER-phagy and ER morphological dynamics as pronounced, underappreciated mechanisms of both normal aging and enhanced longevity.
内质网（ER）由一系列结构不同的亚结构域组成，每个亚结构域都有其独特的功能。虽然内质网相关过程的改变与衰老相关的发病机制有关，但内质网形态的变化是否是这些功能改变的基础尚不清楚。我们报告称，内质网重塑是从酵母到人类及哺乳动物等模型中衰老过程的一个保守特征。以秀丽隐杆线虫作为后生动物衰老的一个范例，我们发现随着动物年龄的增长，几乎所有组织中的内质网质量都会下降，内质网形态也会从粗糙的片层结构转变为管状内质网。蛋白质组组成随之发生的大规模变化对应于内质网从蛋白质合成向脂质代谢的转变。为了推动这种实质性的重塑，内质网自噬在成年早期被激活，以应对内质网腔中蛋白质折叠负担的增加和整体蛋白质合成的减少，从而促进粗糙内质网的更新。令人惊讶的是，内质网重塑是衰老过程中的一种主动且具有保护作用的反应，因为内质网自噬功能受损会限制酵母的寿命，而多种延长寿命的模式即使在幼龄动物中也会促进内质网形态的深刻重塑。我们的研究结果共同揭示了内质网自噬和内质网形态动力学是正常衰老和延长寿命过程中显著但未被充分认识的机制。
