bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022–07–03
eight papers selected by
Verena Kohler, Stockholm University
  1. Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites.
  2. Cvm1 is a component of multiple vacuolar contact sites required for sphingolipid homeostasis.
  3. Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease.
  4. The mitochondrial associated endoplasmic reticulum membranes: A platform for the pathogenesis of inflammation-mediated metabolic diseases.
  5. VAP Proteins - From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease.
  6. Three-dimensional Characterization of Interorganelle Contact Sites in Hepatocytes using Serial Section Electron Microscopy.
  7. Single Image Capture of Bioactive Ion Crosstalk within Inter-Organelle Membrane Contacts at Nanometer Resolution.
  8. Icariin inhibits the formation of mitochondria-associated membranes (MAMs) and improves erectile function in rats treated with prostate radiation.
  1. Nat Commun. 2022 Jun 28. 13(1): 3702
    Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites.
    Hyunwoo Kim, Seowhang Lee, Youngsoo Jun, Changwook Lee.
      The endoplasmic reticulum (ER)-mitochondria contact site (ERMCS) is crucial for exchanging biological molecules such as phospholipids and Ca2+ ions between these organelles. Mitoguardin-2 (MIGA2), a mitochondrial outer membrane protein, forms the ERMCS in higher eukaryotic cells. Here, we report the crystal structures of the MIGA2 Lipid Droplet (LD) targeting domain and the ER membrane protein VAPB bound to the phosphorylated FFAT motif of MIGA2. These structures reveal that the MIGA2 LD targeting domain has a large internal hydrophobic pocket that accommodates phospholipids and that two phosphorylations of the FFAT motif are required for tight interaction of MIGA2 with VAPB, which enhances the rate of lipid transport. Further biochemical studies show that MIGA2 transports phospholipids between membranes with a strong preference for binding and trafficking phosphatidylserine (PS). These results provide a structural and molecular basis for understanding how MIGA2 mediates the formation of ERMCS and facilitates lipid trafficking at the ERMCS.
    DOI:  https://doi.org/10.1038/s41467-022-31462-6
  2. J Cell Biol. 2022 Aug 01. pii: e202103048. [Epub ahead of print]221(8):
    Cvm1 is a component of multiple vacuolar contact sites required for sphingolipid homeostasis.
    Daniel D Bisinski, Inês Gomes Castro, Muriel Mari, Stefan Walter, Florian Fröhlich, Maya Schuldiner, Ayelén González Montoro.
      Membrane contact sites are specialized platforms formed between most organelles that enable them to exchange metabolites and influence the dynamics of each other. The yeast vacuole is a degradative organelle equivalent to the lysosome in higher eukaryotes with important roles in ion homeostasis and metabolism. Using a high-content microscopy screen, we identified Ymr160w (Cvm1, for contact of the vacuole membrane 1) as a novel component of three different contact sites of the vacuole: with the nuclear endoplasmic reticulum, the mitochondria, and the peroxisomes. At the vacuole-mitochondria contact site, Cvm1 acts as a tether independently of previously known tethers. We show that changes in Cvm1 levels affect sphingolipid homeostasis, altering the levels of multiple sphingolipid classes and the response of sphingolipid-sensing signaling pathways. Furthermore, the contact sites formed by Cvm1 are induced upon a decrease in sphingolipid levels. Altogether, our work identifies a novel protein that forms multiple contact sites and supports a role of lysosomal contacts in sphingolipid homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202103048
  3. Front Mol Biosci. 2022 ;9 908721
    Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease.
    Russell P Saneto, Francisco A Perez.
      Communication between intracellular organelles is essential for overall cellular function. How this communication occurs and under what circumstances alterations transpire are only the beginning to be elucidated. The pathways of calcium homeostasis, lipid transfer, mitochondrial dynamics, and mitophagy/apoptosis have been linked to the endoplasmic reticulum and tethering sites on the outer and/or inner mitochondrial membrane called mitochondria-associated endoplasmic reticulum membranes (MAM). Sensitive visualization by high-powered microscopy coupled with the advent of massive parallel sequencing has elaborated the structure, while patient's diseases have uncovered the physiological function of these networks. Using specific patient examples from our pediatric mitochondrial center, we expand how specific genetic pathological variants in certain MAM structures induce disease. Genetic variants in MICU1, PASC-2, CYP2U1, SERAC1, and TANGO2 can induce early development abnormalities in the areas of cognition, motor, and central nervous system structures across multiple MAM pathways and implicate mitochondrial dysregulation.
    Keywords:  autophagy; calcium; fatty acid metabolism; gene products; metabolism; mitochondria-associated endoplasmic reticulum membrane; phospholipids
    DOI:  https://doi.org/10.3389/fmolb.2022.908721
  4. Immun Inflamm Dis. 2022 Jul;10(7): e647
    The mitochondrial associated endoplasmic reticulum membranes: A platform for the pathogenesis of inflammation-mediated metabolic diseases.
    Sisay T Degechisa, Yosef T Dabi, Solomon T Gizaw.
      Mitochondria-associated endoplasmic reticulum membranes (MAM) are specialized subcellular compartments that are shaped by endoplasmic reticulum (ER) subdomains placed side by side to the outer membrane of mitochondria (OMM) being connected by tethering proteins in mammalian cells. Studies showed that MAM has multiple physiological functions. These include regulation of lipid synthesis and transport, Ca2+ transport and signaling, mitochondrial dynamics, apoptosis, autophagy, and formation and activation of an inflammasome. However, alterations of MAM integrity lead to deleterious effects due to an increased generation of mitochondrial reactive oxygen species (ROS) via increased Ca2+ transfer from the ER to mitochondria. This, in turn, causes mitochondrial damage and release of mitochondrial components into the cytosol as damage-associated molecular patterns which rapidly activate MAM-resident Nod-like receptor protein-3 (NLRP3) inflammasome components. This complex induces the release of pro-inflammatory cytokines that initiate low-grade chronic inflammation that subsequently causes the development of metabolic diseases. But, the mechanisms of how MAM is involved in the pathogenesis of these diseases are not exhaustively reviewed. Therefore, this review was aimed to highlight the contribution of MAM to a variety of cellular functions and consider its significance pertaining to the pathogenesis of inflammation-mediated metabolic diseases.
    Keywords:  ER-stress; MAM; NLRP3-inflammasome; inflammatory mediated metabolic diseases
    DOI:  https://doi.org/10.1002/iid3.647
  5. Front Cell Dev Biol. 2022 ;10 895856
    VAP Proteins - From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease.
    Suzan Kors, Joseph L Costello, Michael Schrader.
      Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are ubiquitous ER-resident tail-anchored membrane proteins in eukaryotic cells. Their N-terminal major sperm protein (MSP) domain faces the cytosol and allows them to interact with a wide variety of cellular proteins. Therefore, VAP proteins are vital to many cellular processes, including organelle membrane tethering, lipid transfer, autophagy, ion homeostasis and viral defence. Here, we provide a timely overview of the increasing number of VAPA/B binding partners and discuss the role of VAPA/B in maintaining organelle-ER interactions and cooperation. Furthermore, we address how viruses and intracellular bacteria hijack VAPs and their binding partners to induce interactions between the host ER and pathogen-containing compartments and support pathogen replication. Finally, we focus on the role of VAP in human disease and discuss how mutated VAPB leads to the disruption of cellular homeostasis and causes amyotrophic lateral sclerosis.
    Keywords:  FFAT motif; VAPA; VAPB; amyotrophic lateral scelerosis; endoplasmic reticulum; membrane contact sites; pathogen-host interactions; peroxisomes
    DOI:  https://doi.org/10.3389/fcell.2022.895856
  6. J Vis Exp. 2022 Jun 09.
    Three-dimensional Characterization of Interorganelle Contact Sites in Hepatocytes using Serial Section Electron Microscopy.
    Gary Hong Chun Chung, Paul Gissen, Christopher J Stefan, Jemima J Burden.
      Transmission electron microscopy has been long considered to be the gold standard for the visualization of cellular ultrastructure. However, analysis is often limited to two dimensions, hampering the ability to fully describe the three-dimensional (3D) ultrastructure and functional relationship between organelles. Volume electron microscopy (vEM) describes a collection of techniques that enable the interrogation of cellular ultrastructure in 3D at mesoscale, microscale, and nanoscale resolutions. This protocol provides an accessible and robust method to acquire vEM data using serial section transmission EM (TEM) and covers the technical aspects of sample processing through to digital 3D reconstruction in a single, straightforward workflow. To demonstrate the usefulness of this technique, the 3D ultrastructural relationship between the endoplasmic reticulum and mitochondria and their contact sites in liver hepatocytes is presented. Interorganelle contacts serve vital roles in the transfer of ions, lipids, nutrients, and other small molecules between organelles. However, despite their initial discovery in hepatocytes, there is still much to learn about their physical features, dynamics, and functions. Interorganelle contacts can display a range of morphologies, varying in the proximity of the two organelles to one another (typically ~10-30 nm) and the extent of the contact site (from punctate contacts to larger 3D cisternal-like contacts). The examination of close contacts requires high-resolution imaging, and serial section TEM is well suited to visualize the 3D ultrastructural of interorganelle contacts during hepatocyte differentiation, as well as alterations in hepatocyte architecture associated with metabolic diseases.
    DOI:  https://doi.org/10.3791/63496
  7. Small Methods. 2022 Jul 01. e2200321
    Single Image Capture of Bioactive Ion Crosstalk within Inter-Organelle Membrane Contacts at Nanometer Resolution.
    Guiqian Fang, Huimin Chen, Xintian Shao, Han Wang, Dongxue Zhan, Ran Wang, Peng Meng, Hongbao Fang, Fei Liu, Peixue Ling, Zhongyu Wu, Jiajie Diao, Qingqiang Yao, Qixin Chen.
      Rapid bioactive ion exchange is a form of communication that regulates a wide range of biological processes. Despite advances in super-resolution optical microscopy, visualizing ion exchange remains challenging due to the extremely fast nature of these events. Here, a "converting a dynamic event into a static image construction" (CDtSC) strategy is developed that uses the color transformation of a single dichromatic molecular probe to visualize bioactive ion inter-organelle exchange in live cells. As a proof of concept, a reactive sulfur species (RSS) is analyzed at the mitochondria-lysosome contact sites (MLCs). A non-toxic and sensitive probe based on coumarin-hemicyanine structure is designed that responds to RSS localized in both mitochondria and lysosomes while fluorescing different colors. Using this probe, RSS give-and-take at MLCs is visualized, thus providing the first evidence that RSS is involved in inter-organelle contacts and communication. Taken together, the CDtSC provides a strategy to visualize and analyze rapid inter-organelle ion exchange events in live cells at nanometer resolution.
    Keywords:  bioactive ions; live cell imaging; mitochondria-lysosome contact sites; multi-labeling; super-resolution microscopy
    DOI:  https://doi.org/10.1002/smtd.202200321
  8. Andrology. 2022 Jun 28.
    Icariin inhibits the formation of mitochondria-associated membranes (MAMs) and improves erectile function in rats treated with prostate radiation.
    Chang-Jian Deng, Xiong Li, Yang Zeng, Jun Jiang, Rui Jiang.
       BACKGROUND: Erectile function is usually impaired after radiation therapy in prostate cancer patients. eNOS is a key enzyme in the process of erection. Mitochondria-associated membranes (MAMs) are closely contacted with the production and bioactivity of eNOS.
    OBJECTIVE: To study the mechanism of icariin improves the erectile function of rats treated with prostate radiation by controling the expression of MAMs in penile corpus cavernosum.
    METHODS: Twenty 8-week-old healthy male SD rats were randomized to four groups: control group, radiation therapy (RT) group, icariin (10 mg/kg/d gavage) group, and RT + icariin (10 mg/kg/d gavage) group (n = 5). In RT group and RT + icariin group, rats were irradiated with X-rays to the prostate region (total dose 37.5 gray; 7.5 gray/day for 5 days). The ICPmax/MAP, NO concentration and the level of IP3 R1, PACS2, FACL4, nNOS, p-eNOS, and eNOS in rats' penile cavernous tissue was determined 9 weeks after radiation therapy.
    RESULTS: Compared with the control group and the RT + icariin group, the ICPmax/MAP of the RT group was remarkably reduced (P<0.05). The levels of p-eNOS/eNOS, nNOS and the concentration of NO in the penile cavernous tissue of the penis in the RT group were remarkably decreased compared to the control group and the RT + icariin group (P<0.05). The levels of IP3 R1, PACS2, and FACL4 in penile cavernous tissue of the RT group were significantly higher than those in the control group and the RT + icariin group (P<0.05).
    CONCLUSIONS: After prostate X-ray radiotherapy in rats, the formation of MAMs may be increased by increased expression of IP3 R1, PACS2, and FACL4 in penile cavernous tissue, resulting in impaired erectile function. Icariin might increase p-eNOS/eNOS and improve erectile function in rats after prostate radiotherapy by inhibiting the expression of IP3 R1, PACS2, and FACL4. This article is protected by copyright. All rights reserved.
    Keywords:  Icariin; mitochondria-associated membrane; nitric oxide synthase; radiation
    DOI:  https://doi.org/10.1111/andr.13218
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