Phospholipid transport across the IMS. Ups/PRELI family contributes to PA and PS transport between the OMM and IMM. Once lipid is extracted from the OMM and incorporated into the pocket of the transfer protein, Ups/PRELI associates with Mdm35/TRIAP1 and closes its lid, enabling efficient transport. Upon reaching the IMM, the protein complex dissociates, facilitating lipid release. Ups/PRELI proteins are then subjected to proteolytic degradation. (A) A positively charged residue (K58) at the bottom of Ups1/PRELID1’s cavity interacts with the PA head group. PA is extracted from OMM in a process that is perhaps facilitated by the cone-shaped structure of PA that prevents tight packing. The high CL concentration in the IMM helps recruit Ups1/PRELID1. PA transport is stimulated and repressed by high PA and high CL levels, respectively. (B) PS transport by Ups2-Mdm35/PRELID3b-TRIAP1 permits PE production in the IMM. The greater hydrophobicity of the Ω loop and the α3 helix of PRELID3b aids in PS extraction from OMM, even though its cylindrical structure does not support its extraction. High CL amounts promote PS translocation.