FIGURE 3.

Inter-organelle and intra-organelle phospholipid trafficking. The existence of ER- and vacuole-mitochondria contacts is highly conserved from yeast to humans. By generating closely appositioned membranes, the inter-organelle and intra-organelle tethers are hypothesized to promote movement of lipids across the aqueous cytosol and IMS, respectively. Within the mitochondrion, phospholipid trafficking may involve contacts between the OMM and the IMM mediated by MICOS complexes or NM23-H4. In addition, PRELI transports PA from the OMM to the IMM. PLS3 activity stimulates CL externalization on OMM. It may directly transport CL from the IMM to the OMM or instead function as a scramblase that redistributes CL between both leaflets of the IMM. CL now exposed to IMS-side of IMM would then be transported to the OMM by other mechanisms. With the possible exception of EMC, it is presently unclear if any of the known tethers has specificity for a defined phospholipid(s); as such, they are shown to promote the flux of phospholipids (PLs) in bulk. If a specific phospholipid is impacted by mutations in a complex/protein (levels and/or composition), the lipid is indicated. Solid lines indicate known transport mechanisms. Dashed lines describe possible trafficking routes and/or highlight transport events whose mechanisms have not been resolved. The ERMES complex is found only in yeast and color-coded pink. For the remaining proteins/complexes, those found only in mammals are in blue and those that are likely to be conserved across species are colored gray. See text for additional details.