Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France; Inserm U1280, 91198 Gif-sur-Yvette Cedex, France.
Minerva Foundation Institute for Medical Research, Biomedicum 2U, 00290 Helsinki, Finland.
Cell Rep. 2022 Sep 20;40(12):111364. doi: 10.1016/j.celrep.2022.111364.
Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.
线粒体是细胞生存所必需的动态细胞器，其结构和功能的完整性依赖于内质网（ER）和线粒体膜间隙之间脂质的选择性和调节性运输。由于它们之间没有通过囊泡运输连接，因此 ER 和线粒体之间的脂质交换发生在膜接触位点。然而，这些过程中涉及的机制和蛋白质才刚刚开始出现。在这里，我们表明脂质转移蛋白 ORP5 和 ORP8 的主要生理定位是在与线粒体相关的内质网膜（MAM）亚区，与桥接两个线粒体膜的线粒体间空间桥接（MIB）/线粒体接触位点和嵴连接组织系统（MICOS）复合物物理相连。我们还表明，ORP5/ORP8 通过与 MIB/MICOS 复合物合作，介导磷脂酰丝氨酸（PS）脂质从 ER 向线粒体的非囊泡运输。总的来说，我们的研究揭示了 ER-线粒体接触参与脂质转移和由 MIB/MICOS 复合物维持的线粒体内部膜接触之间的物理和功能联系。
