A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria

Abstract

Tethering of the endoplasmic reticulum to mitochondria by a conserved endoplasmic reticulum complex is needed for the transfer of phospholipids between these organelles.

Abstract

Mitochondrial membrane biogenesis and lipid metabolism require phospholipid transfer from the endoplasmic reticulum (ER) to mitochondria. Transfer is thought to occur at regions of close contact of these organelles and to be nonvesicular, but the mechanism is not known. Here we used a novel genetic screen in S. cerevisiae to identify mutants with defects in lipid exchange between the ER and mitochondria. We show that a strain missing multiple components of the conserved ER membrane protein complex (EMC) has decreased phosphatidylserine (PS) transfer from the ER to mitochondria. Mitochondria from this strain have significantly reduced levels of PS and its derivative phosphatidylethanolamine (PE). Cells lacking EMC proteins and the ER–mitochondria tethering complex called ERMES (the ER–mitochondria encounter structure) are inviable, suggesting that the EMC also functions as a tether. These defects are corrected by expression of an engineered ER–mitochondrial tethering protein that artificially tethers the ER to mitochondria. EMC mutants have a significant reduction in the amount of ER tethered to mitochondria even though ERMES remained intact in these mutants, suggesting that the EMC performs an additional tethering function to ERMES. We find that all Emc proteins interact with the mitochondrial translocase of the outer membrane (TOM) complex protein Tom5 and this interaction is important for PS transfer and cell growth, suggesting that the EMC forms a tether by associating with the TOM complex. Together, our findings support that the EMC tethers ER to mitochondria, which is required for phospholipid synthesis and cell growth.

Author Summary

Mitochondrial membrane biogenesis and lipid metabolism depend on the transfer of phospholipid from the endoplasmic reticulum to mitochondria. This transfer is thought to occur at regions where these organelles are in close contact, and, although the process is thought not to involve vesicles, the mechanism is not known. In this study, we found a complex of proteins in the endoplasmic reticulum that is required for the transfer of one phospholipid—phosphatidylserine—from the endoplasmic reticulum to mitochondria. Cells lacking this protein complex have nonfunctional mitochondria with an abnormal lipid composition. We show that the complex is required to maintain close contacts between the endoplasmic reticulum and mitochondria; the complex probably directly interacts with at least one protein on the surface of mitochondria. In addition, cells lacking this complex and a second previously identified tethering complex are not viable. Thus, our findings suggest that tethering of the endoplasmic reticulum and mitochondria is essential for cell growth, likely because it is necessary for lipid exchange between these organelles.