ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine

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 mito-chondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids be-tween 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 local-ization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) sub -domains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial mem-branes. 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-mitochon-drial membrane contacts maintained by the MIB/MICOS complexes.

Automated summary

Mitochondria and the endoplasmic reticulum exchange lipids at membrane contact sites, and the proteins ORP5 and ORP8 play a key role in this process by mediating non-vesicular transport of phosphatidylserine (PS) lipids with the help of the MIB/MICOS complexes.