Molecular species selectivity of lipid transport creates a mitochondrial sink for di‐unsaturated phospholipids
Mike F. Renne, Xue Bao, Margriet Hokken, Dolf Bierhuizen, Martin Hermansson, Richard R. Sprenger, Tom A. Ewing, Xiao Ma, Ruud C. Cox, Jos F. Brouwers, Cedric H. De Smet, Christer S. Ejsing, Anton I.P.M. de Kroon
Abstract
Mitochondria depend on the import of phospholipid precursors for the biosynthesis of phosphatidylethanolamine (PE) and cardiolipin, yet the mechanism of their transport remains elusive. A dynamic lipidomics approach revealed that mitochondria preferentially import di‐unsaturated phosphatidylserine (PS) for subsequent conversion to PE by the mitochondrial PS decarboxylase Psd1p. Several protein complexes tethering mitochondria to the endomembrane system have been implicated in lipid transport in yeast, including the endoplasmic reticulum (ER)‐mitochondrial encounter structure (ERMES), ER‐membrane complex (EMC), and the vacuole and mitochondria patch (vCLAMP). By limiting the availability of unsaturated phospholipids, we created conditions to investigate the mechanism of lipid transfer and the contributions of the tethering complexes in vivo. Under these conditions, inactivation of ERMES components or of the vCLAMP component Vps39p exacerbated accumulation of saturated lipid acyl chains, indicating that ERMES and Vps39p contribute to the mitochondrial sink for unsaturated acyl chains by mediating transfer of di‐unsaturated phospholipids. These results support the concept that intermembrane lipid flow is rate‐limited by molecular species‐dependent lipid efflux from the donor membrane and driven by the lipid species’ concentration gradient between donor and acceptor membrane. Mitochondrial phospholipid synthesis depends on phospholipid import occurring at organelle contact sites, yet the molecular mechanism of lipid transport remains elusive. Here, lipid transport into mitochondria is shown to be molecular species‐selective, with preferential uptake of di‐unsaturated phospholipids enriching the mitochondrial membranes in unsaturated lipid acyl chains. Mitochondrial lipid import at organelle contact sites is phospholipid molecular species‐selective, enriching mitochondria in unsaturated lipids.