bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022–05–08
eight papers selected by
Verena Kohler, Stockholm University
  1. A novel superfamily of bridge-like lipid transfer proteins.
  2. SHIP164 is a chorein motif lipid transfer protein that controls endosome-Golgi membrane traffic.
  3. The involvement of oxysterol-binding protein related protein (ORP) 6 in the counter-transport of phosphatidylinositol-4-phosphate (PI4P) and phosphatidylserine (PS) in neurons.
  4. Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.
  5. Editorial: Lipids and Membrane Contacts in Yeast-Structure, Functional Aspects and Implications on Ageing, Cell Death and Autophagy.
  6. Erratum for Cadena et al., "Mitochondrial Contact Site and Cristae Organization System and F1FO-ATP Synthase Crosstalk Is a Fundamental Property of Mitochondrial Cristae".
  7. The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.
  8. The endoplasmic reticulum membrane protein complex localizes to the mitochondrial - endoplasmic reticulum interface and its subunits modulate phospholipid biosynthesis in Trypanosoma brucei.
  1. Trends Cell Biol. 2022 Apr 28. pii: S0962-8924(22)00083-6. [Epub ahead of print]
    A novel superfamily of bridge-like lipid transfer proteins.
    Sarah D Neuman, Tim P Levine, Arash Bashirullah.
      Lipid transfer proteins mediate nonvesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Recently, a new type of bridge-like lipid transfer protein has emerged; these proteins contain a long hydrophobic groove and can mediate bulk transport of lipids between organelles. Here, we review recent insights into the structure of these proteins and identify a repeating modular unit that we propose to name the repeating β-groove (RBG) domain. This new structural understanding conceptually unifies all the RBG domain-containing lipid transfer proteins as members of an RBG protein superfamily. We also examine the biological functions of these lipid transporters in normal physiology and disease and speculate on the evolutionary origins of RBG proteins in bacteria.
    Keywords:  AlphaFold; Vps13; autophagy; lipid transfer proteins; lipids; membrane contact sites
    DOI:  https://doi.org/10.1016/j.tcb.2022.03.011
  2. J Cell Biol. 2022 Jun 06. pii: e202111018. [Epub ahead of print]221(6):
    SHIP164 is a chorein motif lipid transfer protein that controls endosome-Golgi membrane traffic.
    Michael G Hanna, Patreece H Suen, Yumei Wu, Karin M Reinisch, Pietro De Camilli.
      Cellular membranes differ in protein and lipid composition as well as in the protein-lipid ratio. Thus, progression of membranous organelles along traffic routes requires mechanisms to control bilayer lipid chemistry and their abundance relative to proteins. The recent structural and functional characterization of VPS13-family proteins has suggested a mechanism through which lipids can be transferred in bulk from one membrane to another at membrane contact sites, and thus independently of vesicular traffic. Here, we show that SHIP164 (UHRF1BP1L) shares structural and lipid transfer properties with these proteins and is localized on a subpopulation of vesicle clusters in the early endocytic pathway whose membrane cargo includes the cation-independent mannose-6-phosphate receptor (MPR). Loss of SHIP164 disrupts retrograde traffic of these organelles to the Golgi complex. Our findings raise the possibility that bulk transfer of lipids to endocytic membranes may play a role in their traffic.
    DOI:  https://doi.org/10.1083/jcb.202111018
  3. Biochem Biophys Rep. 2022 Jul;30 101257
    The involvement of oxysterol-binding protein related protein (ORP) 6 in the counter-transport of phosphatidylinositol-4-phosphate (PI4P) and phosphatidylserine (PS) in neurons.
    Shinya Mochizuki, Harukata Miki, Ruyun Zhou, Yasuko Noda.
      Oxysterol-binding protein (OSBP)-related protein (ORP) 6, a member of subfamily III in the ORP family, localizes to membrane contact sites between the endoplasmic reticulum (ER) and other organelles and functions in non-vesicular exchange of lipids including phosphatidylinositol-4-phosphate (PI4P) in neurons. In this study, we searched for the lipid counter-transported in exchange for PI4P by using molecular cell biology techniques. Deconvolution microscopy revealed that knockdown of ORP6 partially shifted localization of a phosphatidylserine (PS) marker but not filipin in primary cultured cerebellar neurons. Overexpression of ORP6 constructs lacking the OSBP-related ligand binding domain (ORD) resulted in the same shift of the PS marker. A PI4KⅢα inhibitor specifically inhibiting the synthesis and plasma membrane (PM) localization of PI4P, suppressed the localization of ORP6 and the PS marker at the PM. Overexpression of mutant PS synthase 1 (PSS1) inhibited transport of the PS marker to the PM and relocated the PI4P marker to the PM in Neuro-2A cells. Introduction of ORP6 but not the dominant negative ORP6 constructs, shifted the localization of PS back to the PM. These data collectively suggest the involvement of ORP6 in the counter-transport of PI4P and PS.
    Keywords:  Counter-transport; Membrane contact site; ORP6; Oxysterol; Oxysterol-binding protein; PI4P; PS
    DOI:  https://doi.org/10.1016/j.bbrep.2022.101257
  4. Cell Death Dis. 2022 May 04. 13(5): 436
    Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.
    Rachel J Carter, Mateus Milani, Alison J Beckett, Shiyu Liu, Ian A Prior, Gerald M Cohen, Shankar Varadarajan.
      The recruitment of DRP1 to mitochondrial membranes prior to fission is facilitated by the wrapping of endoplasmic reticulum (ER) membranes around the mitochondria. To investigate the complex interplay between the ER membranes and DRP1 in the context of mitochondrial structure and function, we downregulate two key ER shaping proteins, RTN4 and CLIMP-63, and demonstrate pronounced mitochondrial hyperfusion and reduced ER-mitochondria contacts, despite their differential regulation of ER architecture. Although mitochondrial recruitment of DRP1 is unaltered in cells lacking RTN4 or CLIMP-63, several aspects of mitochondrial function, such as mtDNA-encoded translation, respiratory capacity and apoptosis are significantly hampered. Further mechanistic studies reveal that CLIMP-63 is required for cristae remodeling (OPA1 proteolysis) and DRP1-mediated mitochondrial fission, whereas both RTN4 and CLIMP-63 regulate the recruitment of BAX to ER and mitochondrial membranes to enable cytochrome c release and apoptosis, thereby performing novel and distinct roles in the regulation of mitochondrial structure and function.
    DOI:  https://doi.org/10.1038/s41419-022-04869-8
  5. Front Cell Dev Biol. 2022 ;10 881666
    Editorial: Lipids and Membrane Contacts in Yeast-Structure, Functional Aspects and Implications on Ageing, Cell Death and Autophagy.
    Patrick Rockenfeller, Christopher T Beh, Alexandre Toulmay.
      
    Keywords:  autophagy; cell death; lipid droplet (LD); lipid trafficking and metabolism; membrane contact site (MCS)
    DOI:  https://doi.org/10.3389/fcell.2022.881666
  6. mSphere. 2022 May 02. e0018922
    Erratum for Cadena et al., "Mitochondrial Contact Site and Cristae Organization System and F1FO-ATP Synthase Crosstalk Is a Fundamental Property of Mitochondrial Cristae".
    Lawrence Rudy Cadena, Ondřej Gahura, Brian Panicucci, Alena Zíková, Hassan Hashimi.
      
    DOI:  https://doi.org/10.1128/msphere.00189-22
  7. Commun Biol. 2022 May 06. 5(1): 423
    The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.
    Yinbo Huo, Weiping Sun, Tiezhu Shi, Song Gao, Min Zhuang.
      Mitochondria and peroxisomes are two types of functionally close-related organelles, and both play essential roles in lipid and ROS metabolism. However, how they physically interact with each other is not well understood. In this study, we apply the proximity labeling method with peroxisomal proteins and report that mitochondrial protein mitofusins (MFNs) are in proximity to peroxisomes. Overexpression of MFNs induces not only the mitochondria clustering but also the co-clustering of peroxisomes. We also report the enrichment of MFNs at the mitochondria-peroxisome interface. Induced mitofusin expression gives rise to more mitochondria-peroxisome contacting sites. Furthermore, the tethering of peroxisomes to mitochondria can be inhibited by the expression of a truncated MFN2, which lacks the transmembrane region. Collectively, our study suggests MFNs as regulators for mitochondria-peroxisome contacts. Our findings are essential for future studies of inter-organelle metabolism regulation and signaling, and may help understand the pathogenesis of mitofusin dysfunction-related disease.
    DOI:  https://doi.org/10.1038/s42003-022-03377-x
  8. PLoS Pathog. 2022 May 02. 18(5): e1009717
    The endoplasmic reticulum membrane protein complex localizes to the mitochondrial - endoplasmic reticulum interface and its subunits modulate phospholipid biosynthesis in Trypanosoma brucei.
    Advaitha Iyer, Moritz Niemann, Mauro Serricchio, Caroline E Dewar, Silke Oeljeklaus, Luce Farine, Bettina Warscheid, André Schneider, Peter Bütikofer.
      The endoplasmic reticulum membrane complex (EMC) is a versatile complex that plays a key role in membrane protein biogenesis in the ER. Deletion of the complex has wide-ranging consequences including ER stress, disturbance in lipid transport and organelle tethering, among others. Here we report the function and organization of the evolutionarily conserved EMC (TbEMC) in the highly diverged eukaryote, Trypanosoma brucei. Using (co-) immunoprecipitation experiments in combination with mass spectrometry and whole cell proteomic analyses of parasites after depletion of select TbEMC subunits, we demonstrate that the TbEMC is composed of 9 subunits that are present in a high molecular mass complex localizing to the mitochondrial-endoplasmic reticulum interface. Knocking out or knocking down of single TbEMC subunits led to growth defects of T. brucei procyclic forms in culture. Interestingly, we found that depletion of individual TbEMC subunits lead to disruption of de novo synthesis of phosphatidylcholine (PC) or phosphatidylethanolamine (PE), the two most abundant phospholipid classes in T. brucei. Downregulation of TbEMC1 or TbEMC3 inhibited formation of PC while depletion of TbEMC8 inhibited PE synthesis, pointing to a role of the TbEMC in phospholipid synthesis. In addition, we found that in TbEMC7 knock-out parasites, TbEMC3 is released from the complex, implying that TbEMC7 is essential for the formation or the maintenance of the TbEMC.
    DOI:  https://doi.org/10.1371/journal.ppat.1009717
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