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

细胞器间接触位点几乎存在于细胞的所有区室之间，由于越来越多的生理和代谢过程是通过细胞器之间的物理相互作用来协调的，因此对细胞器间接触位点的研究已成为非常热门的话题。最具特征的细胞器间接触类型之一是发生在线粒体和光滑体之间的接触，它用于交换钙和调节呼吸，Ca2+稳态和信号传导，磷脂生物合成等。然而，可以发现线粒体也与含有核糖体的rough相关，但这种关联的功能尚不清楚，并且这种线粒体相关的rough （mt-rER）是否是一种特殊类型的ER仍有待确定。

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.