bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–03–24
thirteen papers selected by
Verena Kohler, Umeå University
  1. Plastid Transient and Stable Interactions with Other Cell Compartments.
  2. Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.
  3. ER-organelle contacts: A signaling hub for neurological diseases.
  4. A genetic screen to uncover mechanisms underlying lipid transfer protein function at membrane contact sites.
  5. Analysis of a Super-Complex at Contact Sites Between Mitochondria and Plastids.
  6. DGARM/C10orf76/ARMH3 for Ceramide Transfer Zone at the Endoplasmic Reticulum-Distal Golgi Contacts.
  7. Mitochondria-ER contact sites expand during mitosis.
  8. Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.
  9. Structural insights into human EMC and its interaction with VDAC.
  10. Reconstitution of membrane contact by unilamellar vesicles.
  11. Ethanol-Induced Hepatic Ferroptosis Is Mediated by PERK-Dependent MAMs Formation: Preventive Role of Quercetin.
  12. Editorial on Special Collection in Contact: VPS13 and Bridge-Like Lipid Transfer Proteins: A New Mode of Intracellular Continuity.
  13. Simple ammonium salt and sigma-1 receptor ligand dipentylammonium provides neuroprotective effects in cell culture and Caenorhabditis elegans models of Alzheimer's disease.
  1. Methods Mol Biol. 2024 ;2776 107-134
    Plastid Transient and Stable Interactions with Other Cell Compartments.
    Stefanie J Mueller-Schuessele, Sébastien Leterme, Morgane Michaud.
      Plastids are organelles delineated by two envelopes playing important roles in different cellular processes such as energy production or lipid biosynthesis. To regulate their biogenesis and their function, plastids have to communicate with other cellular compartments. This communication can be mediated by metabolites, signaling molecules, and by the establishment of direct contacts between the plastid envelope and other organelles such as the endoplasmic reticulum, mitochondria, peroxisomes, plasma membrane, and the nucleus. These interactions are highly dynamic and respond to different biotic and abiotic stresses. However, the mechanisms involved in the formation of plastid-organelle contact sites and their functions are still far from being understood. In this chapter, we summarize our current knowledge about plastid contact sites and their role in the regulation of plastid biogenesis and function.
    Keywords:  Lipid trafficking; Membrane contact sites; Plastids; Stress response; Stromules
    DOI:  https://doi.org/10.1007/978-1-0716-3726-5_6
  2. Mitochondrion. 2024 Mar 19. pii: S1567-7249(24)00032-1. [Epub ahead of print] 101874
    Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.
    Prakash G Kulkarni, Vaibhavi M Mohire, Pranjal P Waghmare, Tanushree Banerjee.
      Since the discovery of membrane contact sites between ER and mitochondria called mitochondria-associated membranes (MAMs), several pieces of evidence identified their role in the regulation of different cellular processes such as Ca2+ signalling, mitochondrial transport, and dynamics, ER stress, inflammation, glucose homeostasis, and autophagy. The integrity of these membranes was found to be essential for the maintenance of these cellular functions. Accumulating pieces of evidence suggest that MAMs serve as a platform for autophagosome formation. However, the alteration within MAMs' structure is associated with the progression of neurodegenerative diseases. Dysregulated autophagy is a hallmark of neurodegeneration. Here, in this review, we highlight the present knowledge on MAMs, their structural composition, and their roles in different cellular functions. We also discuss the association of MAMs proteins with impaired autophagy and their involvement in the progression of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
    Keywords:  Alzheimer’s disease (AD); Autophagy; Mitochondrial associated membranes (MAMs); Mitophagy; Parkinson’s disease (PD)
    DOI:  https://doi.org/10.1016/j.mito.2024.101874
  3. Pharmacol Res. 2024 Mar 20. pii: S1043-6618(24)00093-8. [Epub ahead of print] 107149
    ER-organelle contacts: A signaling hub for neurological diseases.
    Yunli Wang, Jinghua Yang.
      Neuronal health is closely linked to the homeostasis of intracellular organelles, and organelle dysfunction affects the pathological progression of neurological diseases. In contrast to isolated cellular compartments, a growing number of studies have found that organelles are largely interdependent structures capable of communicating through membrane contact sites (MCSs). MCSs have been identified as key pathways mediating inter-organelle communication crosstalk in neurons, and their alterations have been linked to neurological disease pathology. The endoplasmic reticulum (ER) is a membrane-bound organelle capable of forming an extensive network of pools and tubules with important physiological functions within neurons. There are multiple MCSs between the ER and other organelles and the plasma membrane (PM), which regulate a variety of cellular processes. In this review, we focus on ER-organelle MCSs and their role in a variety of neurological diseases. We compared the biological effects between different tethering proteins and the effects of their respective disease counterparts. We also discuss how altered ER-organelle contacts may affect disease pathogenesis. Therefore, understanding the molecular mechanisms of ER-organelle MCSs in neuronal homeostasis will lay the foundation for the development of new therapies targeting ER-organelle contacts.
    Keywords:  ER-organelle crosstalk; MCSs; neurodegeneration; neurological disorders; tethering proteins
    DOI:  https://doi.org/10.1016/j.phrs.2024.107149
  4. Life Sci Alliance. 2024 Jun;pii: e202302525. [Epub ahead of print]7(6):
    A genetic screen to uncover mechanisms underlying lipid transfer protein function at membrane contact sites.
    Shirish Mishra, Vaishnavi Manohar, Shabnam Chandel, Tejaswini Manoj, Subhodeep Bhattacharya, Nidhi Hegde, Vaisaly R Nath, Harini Krishnan, Corinne Wendling, Thomas Di Mattia, Arthur Martinet, Prasanth Chimata, Fabien Alpy, Padinjat Raghu.
      Lipid transfer proteins mediate the transfer of lipids between organelle membranes, and the loss of function of these proteins has been linked to neurodegeneration. However, the mechanism by which loss of lipid transfer activity leads to neurodegeneration is not understood. In Drosophila photoreceptors, depletion of retinal degeneration B (RDGB), a phosphatidylinositol transfer protein, leads to defective phototransduction and retinal degeneration, but the mechanism by which loss of this activity leads to retinal degeneration is not understood. RDGB is localized to membrane contact sites through the interaction of its FFAT motif with the ER integral protein VAP. To identify regulators of RDGB function in vivo, we depleted more than 300 VAP-interacting proteins and identified a set of 52 suppressors of rdgB The molecular identity of these suppressors indicates a role of novel lipids in regulating RDGB function and of transcriptional and ubiquitination processes in mediating retinal degeneration in rdgB9 The human homologs of several of these molecules have been implicated in neurodevelopmental diseases underscoring the importance of VAP-mediated processes in these disorders.
    DOI:  https://doi.org/10.26508/lsa.202302525
  5. Methods Mol Biol. 2024 ;2776 161-176
    Analysis of a Super-Complex at Contact Sites Between Mitochondria and Plastids.
    Morgane Michaud.
      Plastids are organelles playing fundamental roles in different cellular processes such as energy metabolism or lipid biosynthesis. To fulfill their biogenesis and their function in the cell, plastids have to communicate with other cellular compartments. This communication can be mediated by the establishment of direct contact sites between plastids envelop and other organelles. These contacts are dynamic structures regulated in response to stress. For example, during phosphate (Pi) starvation, the number of contact sites between plastids and mitochondria significantly increases. In this situation, these contacts play an important role in the transfer of galactoglycerolipids from plastids to mitochondria. Recently, Pi starvation stress was used to identify key proteins involved in the traffic of galactoglycerolipids from plastids to mitochondria in Arabidopsis thaliana. A mitochondrial lipoprotein complex called MTL (Mitochondrial Transmembrane Lipoprotein) was identified. This complex contains mitochondrial proteins but also proteins located in the plastid envelope, suggesting its presence at the plastid-mitochondria junction. This chapter describes the protocol to isolate the MTL complex by clear-native polyacrylamide gel electrophoresis (CN-PAGE) from the mitochondrial fraction of Arabidopsis cell cultures and the methods to study different features of this complex.
    Keywords:  Arabidopsis thaliana; CN-PAGE; MTL complex; Membrane contact sites; Mitochondria; Phosphate starvation; Plastids
    DOI:  https://doi.org/10.1007/978-1-0716-3726-5_9
  6. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241239443
    DGARM/C10orf76/ARMH3 for Ceramide Transfer Zone at the Endoplasmic Reticulum-Distal Golgi Contacts.
    Aya Mizuike, Kentaro Hanada.
      Phosphatidylinositol 4-monophosphate (PtdIns(4)P) is one of the key membrane components which mark the membrane contact sites. In the mammalian Golgi complex, PtdIns(4)P is produced at various subregions via specific mechanisms for each site. Particularly, PtdIns(4)P pools generated at the distal Golgi regions are pivotal for the determination of membrane contacts between the endoplasmic reticulum (ER) and Golgi, at which inter-organelle lipid transport takes place. In this short review, we will focus on C10orf76 (or ARMH3), which we propose to rename as DGARM after a distal Golgi armadillo repeat protein, for its function in generating a PtdIns(4)P pool crucial for ER-to-distal Golgi ceramide transport. We further discuss from the viewpoint of the evolutionary conservation of DGARM.
    Keywords:  ACBD3; CERT; PI4KB; lipid transfer proteins; phosphatidylinositol 4-monophosphate; sphingomyelin
    DOI:  https://doi.org/10.1177/25152564241239443
  7. iScience. 2024 Apr 19. 27(4): 109379
    Mitochondria-ER contact sites expand during mitosis.
    Fang Yu, Raphael Courjaret, Lama Assaf, Asha Elmi, Ayat Hammad, Melanie Fisher, Mark Terasaki, Khaled Machaca.
      Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.
    Keywords:  Biological sciences; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109379
  8. Cell Death Discov. 2024 Mar 20. 10(1): 148
    Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.
    Yong Liu, Jin-Ling Huo, Kaidi Ren, Shaokang Pan, Hengdao Liu, Yifeng Zheng, Jingfang Chen, Yingjin Qiao, Yang Yang, Qi Feng.
      Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one of the most serious chronic heart diseases and has become a major cause of heart failure worldwide. At present, the pathogenesis of DCM is unclear, and there is still a lack of effective therapeutics. Previous studies have shown that the homeostasis of mitochondria and the endoplasmic reticulum (ER) play a core role in maintaining cardiovascular function, and structural and functional abnormalities in these organelles seriously impact the occurrence and development of various cardiovascular diseases, including DCM. The interplay between mitochondria and the ER is mediated by the mitochondria-associated ER membrane (MAM), which participates in regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, ER stress, inflammation, and other cellular processes. Recent studies have proven that MAM is closely related to the initiation and progression of DCM. In this study, we aim to summarize the recent research progress on MAM, elaborate on the key role of MAM in DCM, and discuss the potential of MAM as an important therapeutic target for DCM, thereby providing a theoretical reference for basic and clinical studies of DCM treatment.
    DOI:  https://doi.org/10.1038/s41420-024-01918-3
  9. Aging (Albany NY). 2024 Mar 15. 16
    Structural insights into human EMC and its interaction with VDAC.
    Mingyue Li, Chunli Zhang, Yuntao Xu, Shaobai Li, Chenhui Huang, Jian Wu, Ming Lei.
      The endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved, multi-subunit complex acting as an insertase at the ER membrane. Growing evidence shows that the EMC is also involved in stabilizing and trafficking membrane proteins. However, the structural basis and regulation of its multifunctionality remain elusive. Here, we report cryo-electron microscopy structures of human EMC in apo- and voltage-dependent anion channel (VDAC)-bound states at resolutions of 3.47 Å and 3.32 Å, respectively. We discovered a specific interaction between VDAC proteins and the EMC at mitochondria-ER contact sites, which is conserved from yeast to humans. Moreover, we identified a gating plug located inside the EMC hydrophilic vestibule, the substrate-binding pocket for client insertion. Conformation changes of this gating plug during the apo-to-VDAC-bound transition reveal that the EMC unlikely acts as an insertase in the VDAC1-bound state. Based on the data analysis, the gating plug may regulate EMC functions by modifying the hydrophilic vestibule in different states. Our discovery offers valuable insights into the structural basis of EMC's multifunctionality.
    Keywords:  EMC; VDAC; cryo-electron microscopy; gating plug; membrane proteins biogenesis
    DOI:  https://doi.org/10.18632/aging.205660
  10. Biophys Rep. 2023 Aug 31. 9(4): 188-194
    Reconstitution of membrane contact by unilamellar vesicles.
    Shulin Li, Min Zhang, Liang Ge.
      Eukaryotic cells compartmentalize diverse biochemical functions within organelles defined by intracellular membranes. Recent focus has intensified on studying the interactions among organelles and the role of membrane contacts in maintaining cellular balance. While analyzing these contacts mainly involves fluorescence and electron microscopy, as well as biochemical cell fractionation, understanding their mechanisms and responses to genetic and environmental changes remains challenging. Here we describe an approach employing in vitro reconstitution of membrane contacts using unilamellar vesicles. This technique offers insights into contact mechanisms when combined with established methods like fluorescence imaging and mass spectrometry, potentially deepening our understanding of membrane contacts and organelle networks.
    Keywords:  Autophagosome; Autophagy; COPII; ER-Golgi intermediate compartment (ERGIC); ER-exit sites (ERES); Giant unilamellar vesicle (GUV); Liposome; Membrane contacts; Organelle interaction network; SEC12; TMED9
    DOI:  https://doi.org/10.52601/bpr.2023.230011
  11. Mol Nutr Food Res. 2024 Mar 19. e2300343
    Ethanol-Induced Hepatic Ferroptosis Is Mediated by PERK-Dependent MAMs Formation: Preventive Role of Quercetin.
    Hongkun Lin, Xiaoping Guo, Jingjing Liu, Yuhan Tang, Li Chen, Huimin Chen, Ying Zhao, Lili Wang, Hongxia Li, Jiasheng Yu, Ping Yao.
       SCOPE: Iron deposition is frequently observed in alcoholic liver disease (ALD), which indicates a potential role of ferroptosis in its development. This study aims to explore the effects of quercetin on ferroptosis in ALD and elucidates the underlying mechanism involving the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) mediated by protein kinase RNA-like endoplasmic reticulum kinase (PERK).
    METHODS AND RESULTS: C57BL/6J mice are fed either a regular or an ethanol-containing liquid diet (with 28% energy form ethanol) with or without quercetin supplementation (100 mg kg-1 BW) for 12 weeks. Ethanol feeding or treatment induced ferroptosis in mice and AML12 cells, which is associated with increased MAMs formation and PERK expression within MAMs. Quercetin attenuates these changes and protects against ethanol-induced liver injury. The antiferroptotic effect of quercetin is abolished by ferroptosis inducers, but mimicked by ferroptosis inhibitors and PERK knockdown. The study demonstrates that PERK structure, rather than its kinase activity (transfected with the K618A site mutation that inhibits kinase activity-ΔK plasmid or protein C terminal knockout-ΔC plasmid of PERK), mediates the enhanced MAMs formation and ferroptosis during the ethanol exposure.
    CONCLUSION: Quercetin ameliorates ethanol-induced liver injury by inhibiting ferroptosis via modulating PERK-dependent MAMs formation.
    Keywords:  ALD; MAMs; PERK; ferroptosis; quercetin
    DOI:  https://doi.org/10.1002/mnfr.202300343
  12. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241238538
    Editorial on Special Collection in Contact: VPS13 and Bridge-Like Lipid Transfer Proteins: A New Mode of Intracellular Continuity.
    Tim P Levine, Liz Conibear.
      
    DOI:  https://doi.org/10.1177/25152564241238538
  13. Biomed Pharmacother. 2024 Mar 18. pii: S0753-3322(24)00339-1. [Epub ahead of print]173 116455
    Simple ammonium salt and sigma-1 receptor ligand dipentylammonium provides neuroprotective effects in cell culture and Caenorhabditis elegans models of Alzheimer's disease.
    Mani Iyer Prasanth, Kanika Verma, Sirikalaya Brimson, Tewin Tencomnao, James Michael Brimson.
      The sigma-1 receptor (σ-1R), a chaperone protein located at the mitochondria-associated membrane (MAM) of the endoplasmic reticulum, can interact with and modify the signaling pathways of various proteins, thereby modulating many disease pathologies, including Alzheimer's disease (AD). The σ-1R ligand dipentylammonium (DPA) was analyzed for its anti-AD properties using PC12 cells (in vitro) and Caenorhabditis elegans (in vivo) models along with molecular docking (in silico) analysis. DPA at 1 and 10 µM concentrations was able to significantly potentiate NGF-induced neurite growth length by 137.7 ± 12.0 and 187.8 ± 16.4, respectively, when compared to the control 76.9 ± 7.4. DPA also regulated neurite damage caused by Aβ(25-35) treatment in differentiated PC12 cells by improving cell viability and neurite length. In C. elegans, DPA could significantly extend the median and maximum lifespan of Aβ transgenic strain CL2006 without impacting wild-type nematodes. Additionally, it could significantly reduce the paralysis phenotype of another Aβ transgenic strain, CL4176, thereby improving the overall health in AD pathogenesis. This effect depended on σ-1R, as DPA could not modulate the lifespan of σ-1R mutant TM3443. This was further confirmed using agonist PRE084 and antagonist BD1047, wherein the agonist alone could extend the lifespan of CL2006, while the antagonist suppressed the effect of DPA in CL2006. Interestingly, neither had an TM3443. Further, molecular docking analysis showed that DPA had a similar binding affinity as that of PRE084, BD1047 and pentazocine against the σ-1R receptor in humans and C. elegans, which collectively suggests the anti-AD properties of DPA.
    Keywords:  Amyloid-β; C. elegans; DPA; Molecular docking; Neurite outgrowth; PC12 cells; σ-1R
    DOI:  https://doi.org/10.1016/j.biopha.2024.116455
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