Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids

Mike F. Renne*, Xue Bao, Margriet W.J. Hokken, Adolf S. 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


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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.

TidsskriftThe EMBO Journal
Udgave nummer2
Antal sider16
StatusUdgivet - 17. jan. 2022

Bibliografisk note

Funding Information:
We are indebted to Dr. Jodi Nunnari for sharing the PSD mutants. We thank Dr. William Prinz, Dr. Benoît Kornmann, Dr. Steven Claypool, Dr. Takashi Tatsuta, Dr. Karin Athenstaedt, and Dr. Günther Daum for kindly providing strains, plasmids, and antibodies. This research was supported by the Division of Chemical Sciences in the Netherlands, with financial aid from The Netherlands Organization for Scientific Research (NWO) (711‐013‐004, MFR), by the China Scholarship Council (grant no. 201204910146, XB), by the Barth Syndrome Foundation (BSF) (AdK), by a Summer Fellowship from the Federation of European Biochemical Societies (FEBS) (MFR), by the Villum Fonden (Villum Foundation) (VKR023439, C.S.E.), the VILLUM Center for Bioanalytical Sciences (VKR023179, C.S.E.), and the Lundbeckfonden (Lundbeck Foundation) (R54‐A5858, C.S.E.).

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license


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