bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022‒08‒14
nine papers selected by
Verena Kohler
  1. Restructured membrane contacts rewire organelles for human cytomegalovirus infection.
  2. Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions.
  3. The ultrastructural organization of endoplasmic reticulum-plasma membrane contacts is conserved in epithelial cells.
  4. Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
  5. Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels.
  6. Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans.
  7. Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes.
  8. Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans.
  9. Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.
  1. Nat Commun. 2022 Aug 11. 13(1): 4720
    Restructured membrane contacts rewire organelles for human cytomegalovirus infection.
    Katelyn C Cook, Elene Tsopurashvili, Jason M Needham, Sunnie R Thompson, Ileana M Cristea.
      Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested.
    DOI:  https://doi.org/10.1038/s41467-022-32488-6
  2. Cell Death Differ. 2022 Aug 12.
    Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions.
    Qingzhu Chu, Jingru Wang, Yuanjiao Du, Tiantian Zhou, Anbing Shi, Juan Xiong, Wei-Ke Ji, Lin Deng.
      In metazoans the endoplasmic reticulum (ER) undergoes extensive remodeling during the cell cycle. The endosomal sorting complexes required for transport (ESCRT) protein CHMP7 coordinates ESCRT-III dependent nuclear envelope reformation during mitotic exit. However, potential roles of ER-associated CHMP7 at non-mitotic stages remain unclear. Here we discovered a new role of CHMP7 in mediating three-way ER and ER-mitochondrial membrane contact sites (MCSs). We showed that CHMP7 localizes to multiple cellular membranes including the ER, mitochondrial-associated membranes (MAMs) and the outer mitochondrial membrane (OMM) via its N-terminal membrane-binding domain. CHMP7 undergoes dynamic assembly at three-way ER junctions and ER-mitochondrial MCSs through hydrophobic interactions among α helix-1 and α helix-2 of the C-terminal CHMP-like domain, which was required for tethering different organelles in vivo. Furthermore, CHMP7 mediates the formation of three-way ER junctions in parallel with Atlastins (ATLs). Importantly, CHMP7 also regulates ER-mitochondrial interactions and its depletion affects mitochondrial division independently of ESCRT complex. Taken together, our results suggest a direct role of CHMP7 in the formation of the ER contacts in interphase.
    DOI:  https://doi.org/10.1038/s41418-022-01048-2
  3. Mol Biol Cell. 2022 Aug 10. mbcE21110534T
    The ultrastructural organization of endoplasmic reticulum-plasma membrane contacts is conserved in epithelial cells.
    Gary Hong Chun Chung, Maëlle Lorvellec, Paul Gissen, Franck Pichaud, Jemima J Burden, Christopher J Stefan.
      Contacts between the endoplasmic reticulum and plasma membrane (ER-PM contacts) have important roles in membrane lipid and calcium dynamics. Yet, their organization in polarized epithelial cells has not been thoroughly described. Here, we examine ER-PM contacts in hepatocytes in mouse liver using electron microscopy, providing the first comprehensive ultrastructural study of ER-PM contacts in a mammalian epithelial tissue. Our quantitative analyses reveal strikingly distinct ER-PM contact architectures spatially linked to apical, lateral, and basal PM domains. Notably, we find that an extensive network of ER-PM contacts exists at lateral PM domains that form inter-cellular junctions between hepatocytes. Moreover, the spatial organization of ER-PM contacts is conserved in epithelial spheroids, suggesting that ER-PM contacts may serve conserved roles in epithelial cell architecture. Consistent with this notion, we show that ORP5 activity at ER-PM contacts modulates apical-basolateral aspect ratio in HepG2 cells. Thus, ER-PM contacts have a conserved distribution and crucial roles in PM domain architecture across epithelial cell types. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E21-11-0534-T
  4. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041261. [Epub ahead of print]
    Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
    Ana Paula Arruda, Güneş Parlakgül.
      The endoplasmic reticulum (ER) is a key organelle involved in the regulation of lipid and glucose metabolism, proteostasis, Ca2+ signaling, and detoxification. The structural organization of the ER is very dynamic and complex, with distinct subdomains such as the nuclear envelope and the peripheral ER organized into ER sheets and tubules. ER also forms physical contact sites with all other cellular organelles and with the plasma membrane. Both form and function of the ER are highly adaptive, with a potent capacity to respond to transient changes in environmental cues such as nutritional fluctuations. However, under obesity-induced chronic stress, the ER fails to adapt, leading to ER dysfunction and the development of metabolic pathologies such as insulin resistance and fatty liver disease. Here, we discuss how the remodeling of ER structure and contact sites with other organelles results in diversification of metabolic function and how perturbations to this structural flexibility by chronic overnutrition contribute to ER dysfunction and metabolic pathologies in obesity.
    DOI:  https://doi.org/10.1101/cshperspect.a041261
  5. J Mol Med (Berl). 2022 Aug 09.
    Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels.
    Michael A van der Kooij, Liliana Rojas-Charry, Maryam Givehchi, Christina Wolf, Diones Bueno, Sabine Arndt, Stefan Tenzer, Lorenzo Mattioni, Giulia Treccani, Annika Hasch, Michael J Schmeisser, Caterina Vianello, Marta Giacomello, Axel Methner.
      Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.
    Keywords:  Brain; Hexokinase; Mice; Mitochondria; Stress
    DOI:  https://doi.org/10.1007/s00109-022-02235-x
  6. J Cell Sci. 2022 Aug 11. pii: jcs.260227. [Epub ahead of print]
    Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans.
    Jae-Sook Park, Yiying Hu, Nancy M Hollingsworth, Gabriel Miltenberger-Miltenyi, Aaron M Neiman.
      VPS13 family proteins form conduits between the membranes of different organelles through which lipids are transferred. In humans there are four VPS13 paralogs each of which is required to prevent a different inherited disorder. VPS13 proteins contain multiple conserved domains. The VAB domain binds to adaptor proteins that recruit VPS13 to specific membrane contact sites. This work demonstrates the importance of a different domain in VPS13A function. The Pleckstrin Homology (PH) domain at the C-terminus of VPS13A is required to form a complex with the XK scramblase and for co-localization of VPS13A with XK within the cell. Mutations in the interaction surface between VPS13A and XK predicted by Alphafold modeling disrupt both complex formation and colocalization of the two proteins. Mutant VPS13A alleles found in patients with VPS13A disease truncate the PH domain. The phenotypic similarities between VPS13A disease and McLeod syndrome caused by mutations in VPS13A and XK, respectively, argue that loss of the VPS13A-XK complex is the basis of both diseases.
    Keywords:  Lipid transport; Neuroacanthocytosis; Neurodegeneration
    DOI:  https://doi.org/10.1242/jcs.260227
  7. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041254. [Epub ahead of print]
    Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes.
    Takuo Osawa, Kazuaki Matoba, Nobuo N Noda.
      Autophagy is an intracellular degradation system involving de novo generation of autophagosomes, which function as a transporting vesicle of cytoplasmic components to lysosomes for degradation. Isolation membranes (IMs) or phagophores, the precursor membranes of autophagosomes, require millions of phospholipids to expand and transform into autophagosomes, with the endoplasmic reticulum (ER) being the primary lipid source. Recent advances in structural and biochemical studies of autophagy-related proteins have revealed their lipid transport activities: Atg2 at the interface between IM and ER possesses intermembrane lipid transfer activities, while Atg9 at IM and VMP1 and TMEM41B at ER possess lipid scrambling activities. In this review, we summarize recent advances in the establishment of the lipid transport activities of these proteins and their collaboration mechanisms for lipid transport between the ER and IM, and further discuss how unidirectional lipid transport from the ER to IM occurs during autophagosome formation.
    DOI:  https://doi.org/10.1101/cshperspect.a041254
  8. Int J Mol Sci. 2022 Jul 28. pii: 8348. [Epub ahead of print]23(15):
    Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans.
    Chaonan Jin, Eric Felli, Naomi Franziska Lange, Annalisa Berzigotti, Jordi Gracia-Sancho, Jean-François Dufour.
      The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER-mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (n = 48) and correlated the results with histological and metabolic syndrome (MetS) features. NAFLD patients were included according to inclusion and exclusion criteria, and then assigned to NAFL (n = 9) and NASH (n = 39) groups. ERMCs density could discriminate NASH from NAFL (sensitivity 61.5%, specificity 100%). ERMCs abundance correlated with hepatocellular ballooning. Moreover, the density of ERMCs increased with an increase in the number of MetS features. In conclusion, ERMCs increased from NAFL to NASH, in parallel with the number of MetS features, supporting a role for this interaction in the pathophysiology of NASH.
    Keywords:  MAFLD; NAFLD; NASH; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.3390/ijms23158348
  9. Mol Neurobiol. 2022 Aug 13.
    Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.
    Piotr Wojtyniak, Anna Boratynska-Jasinska, Karolina Serwach, Joanna Gruszczynska-Biegala, Barbara Zablocka, Jacek Jaworski, Maria Kawalec.
      In attempts to develop effective therapeutic strategies to limit post-ischemic injury, mitochondria emerge as a key element determining neuronal fate. Mitochondrial damage can be alleviated by various mechanisms including mitochondrial network remodelling, mitochondrial elimination and mitochondrial protein biogenesis. However, the mechanisms regulating relationships between these phenomena are poorly understood. We hypothesized that mitofusin 2 (Mfn2), a mitochondrial GTPase involved in mitochondrial fusion, mitochondria trafficking and mitochondria and endoplasmic reticulum (ER) tethering, may act as one of linking and regulatory factors in neurons following ischemic insult. To verify this assumption, we performed temporal oxygen and glucose deprivation (OGD/R) on rat cortical primary culture to determine whether Mfn2 protein reduction affected the onset of mitophagy, subsequent mitochondrial biogenesis and thus neuronal survival. We found that Mfn2 knockdown increased neuronal susceptibility to OGD/R, prevented mitochondrial network remodelling and resulted in prolonged mitophagosomes formation in response to the insult. Next, Mfn2 knockdown was observed to be accompanied by reduced Parkin protein levels and increased Parkin accumulation on mitochondria. As for wild-type neurons, OGD/R insult was followed by an elevated mtDNA content and an increase in respiratory chain proteins. Neither of these phenomena were observed for Mfn2 knockdown neurons. Collectively, our findings showed that Mfn2 in neurons affected their response to mild and transient OGD stress, balancing the extent of defective mitochondria elimination and positively influencing mitochondrial respiratory protein levels. Our study suggests that Mfn2 is one of essential elements for neuronal response to ischemic insult, necessary for neuronal survival.
    Keywords:  Brain ischemia; Mitochondria; Mitochondrial DNA; Mitochondrial biogenesis; Mitofusin 2; Mitophagy; Primary neurons
    DOI:  https://doi.org/10.1007/s12035-022-02981-6
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