The mitochondrial rough-ER (mt-rER), a new type of endoplasmic reticulum: from structure to function

线粒体粗面-ER（mt-rER），一种新型内质网：从结构到功能

• 批准号: RGPIN-2017-06130
• 负责人: PELLEGRINI, Luca
• 金额: $ 2.04万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661847
• 关键词: mitochondrial; rough; ER; mt; rER

Inter-organellar contact sites exist between nearly all the compartments of the cell, and their study has become very topical because more and more physiological and metabolic processes are coordinated by physical interactions between organelles. One of the best characterized type of inter-organellar contact is the one that occurs between mitochondria and the smoothER, which serves to exchange calcium and regulate respiration, Ca2+ homeostasis and signalling, phospholipid biosynthesis, and more. However, mitochondria can be found associated also to the ribosome-containing roughER, but the function of this association is unknown, and whether or not this mitochondria-associated roughER (mt-rER) is a specialized type of ER remains to be determined. ******Here, we share a wealth of compelling preliminary data to propose a research program that has the objective to show that the mt-rER is a structurally distinct type of ER that controls cholesterol and fatty acids synthesis by translating and compartmentalizing the enzymes of their pathway and the lipoproteins that traffic them.******To this goal, we will capitalize on an ad-hoc developed protocol allowing the purification of mouse liver mt-rER and on our experience in cryo-electron microscopy, cryo-electron tomography, 3D imaging, transcriptomics and proteomics to show that:******1: the mt-rER is not connected to the ER network of the cell ***2: the mt-rER has a proteome that is different from that of the ER***3: the contact site between the smoothER and the mitochondrion (known as MAM or MERC) is a subdomain of the mt-rER***4: proteins of the lipids and cholesterol pathway are translated directly at the mt-rER***5: proteins of the lipids and cholesterol pathway are localized at the interface between the mt-rER and the mitochondrion***6: the mt-rER contains an active cholesterol biosynthetic pathway.******Ultimately, this research will show that the juxtaposition between the mt-rER and the mitochondrion serves to compartmentalize substrates, enzymes and precursors of the lipid and cholesterol pathway, thereby explaining how the cell can efficiently synthesize, handle and transport huge amounts of these molecules.******These discoveries will have a major impact for many. For cell biologists, because they will establish the mt-rER as a novel, structurally and functionally distinct type of ER; for cell physiologists, because they will assigning to the mt-rER a key role in putting lipids and cholesterol in circulation through the synthesis of lipoproteins; and for researchers in the MAM/MERC field because they will provide a framework for studying the mechanisms regulating the biogenesis and remodelling of this important sub-cellular compartment.**

细胞的几乎所有隔室之间都存在组织间接触位点，并且它们的研究变得非常局部，因为越来越多的生理和代谢过程通过细胞器之间的物理相互作用协调。最佳特征类型的器官间接触之一是在线粒体和平滑范围之间发生的类型，它可以交换钙并调节呼吸，Ca2+稳态和信号传导，磷脂生物合成等。但是，线粒体也可以与含核糖体更粗糙相关联，但是该关联的功能尚不清楚，并且该线粒体相关的粗糙剂（MT-RER）是否是一种专业的ER类型，仍然有待确定。 ******在这里，我们共享大量引人入胜的初步数据，以提出一项研究计划，该计划的目的是表明MT-RER是一种在结构上不同的ER类型，可以通过翻译和分区化来控制胆固醇和脂肪酸综合其途径的酶和流动它们的脂蛋白。 ，冷冻电子层析成像，3D成像，转录组学和蛋白质组学，以表明：****** 1：MT-RER与细胞的ER网络无连接*** 2：MT-RER具有蛋白质组这与ER *** 3：平滑和线粒体（称为MAM或MERC）之间的接触位点不同是MT-RER *** 4：脂质和胆固醇途径的蛋白质的子域是直接在MT-RER *** 5：脂质和胆固醇途径的蛋白质位于MT-RER和线粒体之间的接口*** 6：MT-RER中含有活性胆固醇生物合成途径。** ** ****最终，这项研究将表明MT rer和线粒体之间的并置可用于将脂质和胆固醇途径的底物，酶和前体划分，从而解释细胞如何有效地合成和运输大量的细胞******这些发现将对许多人产生重大影响。对于细胞生物学家而言，因为它们将在结构和功能上不同的ER类型上建立MT-RER。对于细胞生理学家而言，因为他们将通过合成脂蛋白将脂质和胆固醇分配给将脂质和胆固醇循环中的关键作用。对于MAM/MERC领域的研究人员，他们将提供一个框架，用于研究调节这一重要的亚细胞室的生物发生和重塑的机制。**