bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023‒07‒02
25 papers selected by
Verena Kohler
  1. Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites.
  2. Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.
  3. Complementation Assay Using Fusion of Split-GFP and TurboID (CsFiND) Enables Simultaneous Visualization and Proximity Labeling of Organelle Contact Sites in Yeast.
  4. Extending the Contacts Breaks the Flow.
  5. How Membrane Contact Sites Shape the Phagophore.
  6. α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease.
  7. Regulation of Endosomal Sorting and Maturation by ER-Endosome Contact Sites.
  8. Get Closer to the World of Contact Sites: A Beginner's Guide to Proximity-Driven Fluorescent Probes.
  9. Epigenetic regulation of mitochondrial-endoplasmic reticulum dynamics in kidney diseases.
  10. The Endoplasmic Reticulum-Mitochondria Encounter Structure and its Regulatory Proteins.
  11. Evolutionary History of Oxysterol-Binding Proteins Reveals Complex History of Duplication and Loss in Animals and Fungi.
  12. Sulforaphane modifies mitochondrial-endoplasmic reticulum associations through reductive stress in cardiomyocytes.
  13. Homotypic SCOTIN assemblies form ER-endosome membrane contacts and regulate endosome dynamics.
  14. Molybdenum and/or cadmium induce NLRP3 inflammasome production by causing mitochondria-associated endoplasmic reticulum membrane dysfunction in sheep hepatocytes.
  15. The PH-like Domain of VPS13 Proteins - a Determinant of Localization to the Golgi Apparatus or to the Plasma Membrane.
  16. Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease.
  17. Biological roles of plant synaptotagmins.
  18. Regulation of Plasma Membrane Sterol Homeostasis by Nonvesicular Lipid Transport.
  19. The lipid transfer proteins Nir2 and Nir3 sustain phosphoinositide signaling and actin dynamics during phagocytosis.
  20. Molecular Regulations of FUNDC1 at ER-Mitochondria Contacts Under Hypoxic Stress.
  21. Ca2+ Signalling is a Conserved Game of Contact.
  22. Csf1: A Putative Lipid Transport Protein Required for Homeoviscous Adaptation of the Lipidome.
  23. Bmal1 downregulation leads to diabetic cardiomyopathy by promoting Bcl2/IP3R-mediated mitochondrial Ca2+ overload.
  24. Corrigendum to "Getting in Touch is an Important Step: Control of Metabolism at Organelle Contact Sites".
  25. Sorting (Nexin-13) out Novel Insights into Endolysosomal Cholesterol Export.
  1. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211026505
    Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites.
    Vladimir Zhemkov, Jen Liou, Ilya Bezprozvanny.
      Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains.
    Keywords:  cholesterol; endoplasmic reticulum; lipid microdomains; membrane contact sites; mitochondria-associated membranes; sigma-1 receptor
    DOI:  https://doi.org/10.1177/25152564211026505
  2. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211052392
    Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.
    Maria Livia Sassano, Rita Derua, Etienne Waelkens, Patrizia Agostinis, Alexander R van Vliet.
      We recently reported that the ER stress kinase PERK regulates ER-mitochondria appositions and ER- plasma membrane (ER-PM) contact sites, independent of its canonical role in the unfolded protein response. PERK regulation of ER-PM contacts was revealed by a proximity biotinylation (BioID) approach and involved a dynamic PERK-Filamin A interaction supporting the formation of ER-PM contacts by actin-cytoskeleton remodeling in response to depletion of ER-Ca2+ stores. In this report, we further interrogated the PERK BioID interactome by validating through co-IP experiments the interaction between PERK and two proteins involved in Ca2+ handling and ER-mitochondria contact sites. These included the vesicle associated membrane (VAMP)-associated proteins (VAPA/B) and the main ER Ca2+ pump sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2). These data identify new putative PERK interacting proteins with a crucial role in membrane contact sites and Ca2+ signaling further supporting the uncanonical role of PERK in Ca2+ signaling through membrane contact sites (MCSs).
    Keywords:  ER stress; cell biology; endoplasmic reticulum; mitochondrial associated membranes (MAM); sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)
    DOI:  https://doi.org/10.1177/25152564211052392
  3. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231153621
    Complementation Assay Using Fusion of Split-GFP and TurboID (CsFiND) Enables Simultaneous Visualization and Proximity Labeling of Organelle Contact Sites in Yeast.
    Shintaro Fujimoto, Shinya Tashiro, Yasushi Tamura.
      Numerous studies have revealed that organelle membrane contact sites (MCSs) play important roles in diverse cellular events, including the transport of lipids and ions between connected organelles. To understand MCS functions, it is essential to uncover proteins that accumulate at MCSs. Here, we develop a complementation assay system termed CsFiND (Complementation assay using Fusion of split-GFP and TurboID) for the simultaneous visualization of MCSs and identification of MCS-localized proteins. We express the CsFiND proteins on the endoplasmic reticulum and mitochondrial outer membrane in yeast to verify the reliability of CsFiND as a tool for identifying MCS-localized proteins.
    Keywords:  ERMES; endoplasmic reticulum; mitochondria; split GFP; split TurboID; yeast
    DOI:  https://doi.org/10.1177/25152564231153621
  4. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564221125045
    Extending the Contacts Breaks the Flow.
    Amado Carreras-Sureda, Christopher Henry, Nicolas Demaurex.
      In this news and views, we discuss our recent publication where we described how ER-PM membrane contact sites (MCS) are modulated during store operated calcium entry (SOCE). We also examine why enforcing ER-PM MCS by tethering proteins does not not enhance, but rather inhibits SOCE.
    Keywords:  electron microscopy; endoplasmic reticulum; plasma membrane; store-operated calcium entry (SOCE) (SOC); tether
    DOI:  https://doi.org/10.1177/25152564221125045
  5. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231162495
    How Membrane Contact Sites Shape the Phagophore.
    Cristina Capitanio, Anna Bieber, Florian Wilfling.
      During macroautophagy, phagophores establish multiple membrane contact sites (MCSs) with other organelles that are pivotal for proper phagophore assembly and growth. In S. cerevisiae, phagophore contacts have been observed with the vacuole, the ER, and lipid droplets. In situ imaging studies have greatly advanced our understanding of the structure and function of these sites. Here, we discuss how in situ structural methods like cryo-CLEM can give unprecedented insights into MCSs, and how they help to elucidate the structural arrangements of MCSs within cells. We further summarize the current knowledge of the contact sites in autophagy, focusing on autophagosome biogenesis in the model organism S. cerevisiae.
    Keywords:  ER; autophagy; lipid transfer; membrane contact sites; vacuole
    DOI:  https://doi.org/10.1177/25152564231162495
  6. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221119347
    α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease.
    Adolfo Garcia Erustes, Gabriel Cicolin Guarache, Erika da Cruz Guedes, Anderson Henrique França Figueredo Leão, Gustavo José da Silva Pereira, Soraya Soubhi Smaili.
      Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson's disease pathology.
    Keywords:  Parkinson's disease; calcium; endoplasmic reticulum; mitochondria; mitochondria-ER contact sites; α-synuclein
    DOI:  https://doi.org/10.1177/25152564221119347
  7. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221106046
    Regulation of Endosomal Sorting and Maturation by ER-Endosome Contact Sites.
    Steve Jean, Sonya Nassari.
      Endosomes are a heterogeneous population of intracellular organelles responsible for sorting, recycling, or transporting internalized materials for degradation. Endosomal sorting and maturation are controlled by a complex interplay of regulators, with RAB GTPases and phosphoinositides playing key roles. In this decade, another layer of regulation surfaced with the role played by membrane contact sites between the endoplasmic reticulum (ER) and endosomes. Specific regulators of ER-endosome contact sites or proteins localized at these sites are emerging as modulators of this complex endosomal ballet. In particular, lipid transfer or recruitment of various complexes and enzymes at ER-endosome contact sites play an active role in endosome sorting, scission, and maturation. In this short review, we focus on studies describing ER-endosome contact sites in these three endosomal processes.
    Keywords:  ORP10; OSBP; PIK4IIα/β; TMCC1; TMEM16K; endoplasmic reticulum; endosomes; membrane contact sites; phosphoinositides
    DOI:  https://doi.org/10.1177/25152564221106046
  8. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221135748
    Get Closer to the World of Contact Sites: A Beginner's Guide to Proximity-Driven Fluorescent Probes.
    Elena Poggio, Marisa Brini, Tito Calì.
      To maintain cellular homeostasis and to coordinate the proper response to a specific stimulus, information must be integrated throughout the cell in a well-organized network, in which organelles are the crucial nodes and membrane contact sites are the main edges. Membrane contact sites are the cellular subdomains where two or more organelles come into close apposition and interact with each other. Even though many inter-organelle contacts have been identified, most of them are still not fully characterized, therefore their study is an appealing and expanding field of research. Thanks to significant technological progress, many tools are now available or are in rapid development, making it difficult to choose which one is the most suitable for answering a specific biological question. Here we distinguish two different experimental approaches for studying inter-organelle contact sites. The first one aims to morphologically characterize the sites of membrane contact and to identify the molecular players involved, relying mainly on the application of biochemical and electron microscopy (EM)-related methods. The second approach aims to understand the functional importance of a specific contact, focusing on spatio-temporal details. For this purpose, proximity-driven fluorescent probes are the experimental tools of choice, since they allow the monitoring and quantification of membrane contact sites and their dynamics in living cells under different cellular conditions or upon different stimuli. In this review, we focus on these tools with the purpose of highlighting their great versatility and how they can be applied in the study of membrane contacts. We will extensively describe all the different types of proximity-driven fluorescent tools, discussing their benefits and drawbacks, ultimately providing some suggestions to choose and apply the appropriate methods on a case-to-case basis and to obtain the best experimental outcomes.
    Keywords:  BiFC; FRET; PLA; SPLICS; organelle contact sites
    DOI:  https://doi.org/10.1177/25152564221135748
  9. J Cell Physiol. 2023 Jun 25.
    Epigenetic regulation of mitochondrial-endoplasmic reticulum dynamics in kidney diseases.
    Vishwadeep Shelke, Vinayak Yelgonde, Ajinath Kale, Maciej Lech, Anil Bhanudas Gaikwad.
      Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria-ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria-associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.
    Keywords:  endoplasmic reticulum; epigenetics; kidney diseases; mitochondria; organelle dynamics
    DOI:  https://doi.org/10.1002/jcp.31058
  10. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211064491
    The Endoplasmic Reticulum-Mitochondria Encounter Structure and its Regulatory Proteins.
    Javairia Y Cheema, Jiajia He, Wenfan Wei, Chuanhai Fu.
      In fungi, the endoplasmic reticulum-mitochondria encounter structure (ERMES) is present between the endoplasmic reticulon (ER) and mitochondria to promote the formation of the ER-mitochondria contact sites. Four constitutive components (Mmm1, Mdm12, Mdm34, and Mdm10) assemble to form the ERMES complex while regulator proteins are required for regulating the organization and function of the ERMES complex. Multiple regulator proteins, including Gem1, Lam6, Tom7, and Emr1, of the ERMES complex, have been identified recently. In this review, we discuss the organization of the ERMES complex and the roles of the regulator proteins of the ERMES complex.
    Keywords:  ER; ERMES; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1177/25152564211064491
  11. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564221150428
    Evolutionary History of Oxysterol-Binding Proteins Reveals Complex History of Duplication and Loss in Animals and Fungi.
    Rohan P Singh, Yu-Ping Poh, Savar D Sinha, Jeremy G Wideman.
      Cells maintain the specific lipid composition of distinct organelles by vesicular transport as well as non-vesicular lipid trafficking via lipid transport proteins. Oxysterol-binding proteins (OSBPs) are a family of lipid transport proteins that transfer lipids at various membrane contact sites (MCSs). OSBPs have been extensively investigated in human and yeast cells where 12 have been identified in Homo sapiens and 7 in Saccharomyces cerevisiae. The evolutionary relationship between these well-characterized OSBPs is still unclear. By reconstructing phylogenies of eukaryote OSBPs, we show that the ancestral Saccharomycotina had four OSBPs, the ancestral fungus had five OSBPs, and the ancestral animal had six OSBPs, whereas the shared ancestor of animals and fungi as well as the ancestral eukaryote had only three OSBPs. Our analyses identified three undescribed ancient OSBP orthologues, one fungal OSBP (Osh8) lost in the lineage leading to yeast, one animal OSBP (ORP12) lost in the lineage leading to vertebrates, and one eukaryotic OSBP (OshEu) lost in both the animal and fungal lineages.
    Keywords:  evolutionary cell biology; lipid transport proteins; membrane contact sites; oxysterol-binding proteins; phylogenetics
    DOI:  https://doi.org/10.1177/25152564221150428
  12. Chem Biol Interact. 2023 Jun 27. pii: S0009-2797(23)00283-1. [Epub ahead of print] 110616
    Sulforaphane modifies mitochondrial-endoplasmic reticulum associations through reductive stress in cardiomyocytes.
    Alejandro Silva-Palacios, Arana-Hidalgo Dana, Colín-Val Zaira, Castrejón-Téllez Vicente, Castro-Soria Elizabeth, Pedraza-Chaverri José, López-Marure Rebeca, Zazueta Cecilia.
      Mitochondria-endoplasmic reticulum (ER) communication relies on platforms formed at the ER membrane with the mitochondrial outer membrane contact sites (MERCs). MERCs are involved in several processes including the unfolded protein response (UPR) and calcium (Ca2+) signaling. Therefore, as alterations in MERCs greatly impact cellular metabolism, pharmacological interventions to preserve productive mitochondrial-ER communication have been explored to maintain cellular homeostasis. In this regard, extensive information has documented the beneficial and potential effects of sulforaphane (SFN) in different pathological conditions; however, controversy has arisen regarding the effect of this compound on mitochondria-ER interaction. Therefore, in this study, we investigated whether SFN could induce changes in MERCs under normal culture conditions without damaging stimuli. Our results indicate that non-cytotoxic concentration of 2.5 μM SFN increased ER stress in cardiomyocytes in conjunction with a reductive stress environment, that diminishes ER-mitochondria association. Additionally, reductive stress promotes Ca2+ accumulation in the ER of cardiomyocytes. These data show an unexpected effect of SFN on cardiomyocytes grown under standard culture conditions, promoted by the cellular redox unbalance. Therefore, it is necessary to rationalize the use of compounds with antioxidant properties to avoid triggering cellular side effects.
    Keywords:  Calcium dysregulation; ER stress; MERCs; Reductive stress; Sulforaphane
    DOI:  https://doi.org/10.1016/j.cbi.2023.110616
  13. EMBO Rep. 2023 Jun 28. e56538
    Homotypic SCOTIN assemblies form ER-endosome membrane contacts and regulate endosome dynamics.
    Hyeri Yun, Minkyo Jung, Hojin Lee, Sungjin Jung, Taehyeon Kim, Nari Kim, Seung-Yeol Park, Won Jong Kim, Ji Young Mun, Joo-Yeon Yoo.
      The ER regulates the spatiotemporal organization of endolysosomal systems by membrane contact. In addition to tethering via heterotypic interactions on both organelles, we present a novel ER-endosome tethering mechanism mediated by homotypic interactions. The single-pass transmembrane protein SCOTIN is detected in the membrane of the ER and endosomes. In SCOTIN-knockout (KO) cells, the ER-late endosome contacts are reduced, and the perinuclear positioning of endosomes is disturbed. The cytosolic proline-rich domain (PRD) of SCOTIN forms homotypic assemblies in vitro and is necessary for ER-endosome membrane tethering in cells. A region of 28 amino acids spanning 150-177 within the SCOTIN PRD is essential to elicit membrane tethering and endosomal dynamics, as verified by reconstitution in SCOTIN-KO cells. The assembly of SCOTIN (PRD) is sufficient to mediate membrane tethering, as purified SCOTIN (PRD), but not SCOTIN (PRDΔ150-177), brings two different liposomes closer in vitro. Using organelle-specific targeting of a chimeric PRD domain shows that only the presence on both organellar membranes enables the ER-endosome membrane contact, indicating that the assembly of SCOTIN on heterologous membranes mediates organelle tethering.
    Keywords:  SCOTIN; endoplasmic reticulum; endosome; membrane contact; self-assembly
    DOI:  https://doi.org/10.15252/embr.202256538
  14. Chem Biol Interact. 2023 Jun 27. pii: S0009-2797(23)00284-3. [Epub ahead of print] 110617
    Molybdenum and/or cadmium induce NLRP3 inflammasome production by causing mitochondria-associated endoplasmic reticulum membrane dysfunction in sheep hepatocytes.
    Huifeng Chang, Fan Yang, He Bai, Zengting Lu, Chenghong Xing, Xueyan Dai, Wengen Wan, Shuxian Liao, Huabin Cao.
      Accumulation of the heavy metals molybdenum (Mo) and cadmium (Cd) in the liver can induce organelle damage and inflammation, resulting in hepatotoxicity. The effect of Mo and/or Cd on sheep hepatocytes was investigated by determining the relationship between the mitochondria-associated endoplasmic reticulum membrane (MAM) and NLRP3 inflammasome. Sheep hepatocytes were divided into four groups: the control group, Mo group (600 μM Mo), Cd group (4 μM Cd) and Mo + Cd group (600 μM Mo+4 μM Cd). The results showed that Mo and/or Cd exposure increased the levels of lactate dehydrogenase (LDH) and nitric oxide (NO) in the cell culture supernatant, elevated the levels of intracellular Ca2+ and mitochondrial Ca2+, downregulated the expression of MAM-related factors (IP3R, GRP75, VDAC1, PERK, ERO1-α, Mfn1, Mfn2, ERP44), shortened the length of the MAM and reduced the formation of the MAM structure, eventually causing MAM dysfunction. Moreover, the expression levels of NLRP3 inflammasome-related factors (NLRP3, Caspase1, IL-1β, IL-6, TNF-α) were also dramatically increased after Mo and Cd exposure, triggering NLRP3 inflammasome production. However, an IP3R inhibitor, 2-APB treatment significantly alleviated these changes. Overall, the data indicate that Mo and Cd coexposure leads to structural disruption and dysfunction of MAM, disrupts cellular Ca2+ homeostasis, and increases NLRP3 inflammasome production in sheep hepatocytes. However, the inhibition of IP3R alleviates NLRP3 inflammasome production induced by Mo and Cd.
    Keywords:  Cadmium; Hepatocyte; Mitochondrial-associated endoplasmic reticulum membrane; Molybdenum; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.cbi.2023.110617
  15. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221106024
    The PH-like Domain of VPS13 Proteins - a Determinant of Localization to the Golgi Apparatus or to the Plasma Membrane.
    Joanna Kaminska.
      Mutations in the four human genes VPS13A-D, encoding vacuolar protein sorting 13 (VPS13A-D) proteins, result in developmental or neurodegenerative diseases. Understanding the functioning of VPS13 proteins in physiology and pathology is a hot topic of research. Especially interesting is how VPS13 proteins are localized to specific membrane contact sites and function in lipid transport. Recently, the C-terminal Pleckstrin Homology (PH)-like domains of yeast Vps13 and human VPS13A were found to bind Arf1 GTPase and to phosphoinositol 4,5-bisphosphate. Here, hypotheses on the importance of the dual binding ability of the PH-like domain of VPS13A protein for cell physiology are presented. While yeast Vps13, together with Arf1 GTPase, is important for protein sorting in the Trans Golgi Network (TGN), the localization of VPS13A in TGN is speculated to restrict the binding of VPS13A to the plasma membrane.
    Keywords:  Arf1; Pleckstrin Homology (PH)-like domain; Trans Golgi Network; VPS13 proteins; plasma membrane
    DOI:  https://doi.org/10.1177/25152564221106024
  16. Aging Cell. 2023 Jun 26. e13895
    Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease.
    Daniela Marinho, Ildete Luísa Ferreira, Ricardo Lorenzoni, Sandra M Cardoso, Isabel Santana, A Cristina Rego.
      Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER-mitochondria cross-talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl-H3 in AD human cortex, and increased HDAC2-3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aβ1-42 oligomers (AβO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER-Ca2+ retention and mitochondrial Ca2+ accumulation, mitochondrial depolarization and impaired ER-mitochondria cross-talk, as observed in 3xTg-AD mouse hippocampal neurons and AβO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AβO upon Tac treatment, along with reduction in ER-mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER-mitochondria Ca2+ transfer and mitochondrial Ca2+ retention, while knockdown of HDAC3 decreased ER-Ca2+ accumulation in AβO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aβ levels. These data demonstrate that Tac normalizes Ca2+ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac-mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER-mitochondria communication as a promising target for innovative therapeutics in AD.
    Keywords:  amyloid beta peptide; calcium; histone deacetylases; mitochondria; mitochondrial-associated ER membranes; tacedinaline
    DOI:  https://doi.org/10.1111/acel.13895
  17. Eur J Cell Biol. 2023 Jun 20. pii: S0171-9335(23)00050-X. [Epub ahead of print]102(3): 151335
    Biological roles of plant synaptotagmins.
    Francisco Benitez-Fuente, Miguel A Botella.
      Plant synaptotagmins (SYTs) are resident proteins of the endoplasmic reticulum (ER). They are characterized by an N-terminal transmembrane region and C2 domains at the C-terminus, which tether the ER to the plasma membrane (PM). In addition to their tethering role, SYTs contain a lipid-harboring SMP domain, essential for shuttling lipids between the ER and the PM. There is now abundant literature on Arabidopsis SYT1, the best-characterized family member, which link it to biotic and abiotic responses as well as to ER morphology. Here, we review the current knowledge of SYT members, focusing on their role in stress, and discuss how these roles can be related to their tethering and lipid transport functions. Finally, we contextualize this information about SYTs with their homologs, the yeast tricalbins and the mammalian extended synaptotagmins.
    Keywords:  ER morphology; ER-PM contact sites; Environmental stress; Plant synaptotagmins
    DOI:  https://doi.org/10.1016/j.ejcb.2023.151335
  18. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211042451
    Regulation of Plasma Membrane Sterol Homeostasis by Nonvesicular Lipid Transport.
    Dylan Hong Zheng Koh, Yasunori Saheki.
      Sterol contributes to the structural integrity of cellular membranes and plays an important role in the regulation of cell signaling in eukaryotes. It is either produced in the endoplasmic reticulum or taken up from the extracellular environment. In most eukaryotic cells, however, the majority of sterol is enriched in the plasma membrane. Thus, the transport of sterol between the plasma membrane and other organelles, including the endoplasmic reticulum, is crucial for maintaining sterol homeostasis. While vesicular transport that relies on membrane budding and fusion reactions plays an important role in bulk sterol transport, this mode of transport is slow and non-selective. Growing evidence suggests a critical role of nonvesicular transport mediated by evolutionarily conserved families of lipid transfer proteins in more rapid and selective delivery of sterol. Some lipid transfer proteins act primarily at the sites of contacts formed between the endoplasmic reticulum and other organelles or the plasma membrane without membrane fusion. In this review, we describe the similarities and differences of sterol biosynthesis and uptake in mammals and yeast and discuss the role of their lipid transfer proteins in maintaining plasma membrane sterol homeostasis.
    Keywords:  cholesterol; endoplasmic reticulum; endosome; lipid transfer protein; nonvesicular; plasma membrane
    DOI:  https://doi.org/10.1177/25152564211042451
  19. J Cell Sci. 2023 Jun 28. pii: jcs.260902. [Epub ahead of print]
    The lipid transfer proteins Nir2 and Nir3 sustain phosphoinositide signaling and actin dynamics during phagocytosis.
    Mayis Kaba, Amado Carreras-Sureda, Paula Nunes-Hasler, Nicolas Demaurex.
      Changes in membrane phosphoinositides and local Ca2+ elevations at sites of particle capture coordinate the dynamic remodeling of the actin cytoskeleton during phagocytosis. Here, we show that the phosphatidylinositol (PI) transfer proteins PITPNM1 (Nir2) and PITPNM2 (Nir3) maintain PI(4,5)P2 homeostasis at phagocytic cups, thereby promoting actin contractility and the sealing of phagosomes. Nir3 and to a lesser extent Nir2 accumulated on ER cisternae juxtaposed to phagocytic cups when expressed in phagocytic COS-7 cells. CRISPR-Cas9 editing of Nir2 and Nir3 genes decreased plasma membrane PI(4,5)P2 levels, store-operated Ca2+ entry (SOCE), and receptor-mediated phagocytosis, stalling particle capture at cup stage. Re-expression of either Nir2 or Nir3 restored phagocytosis, but not SOCE, proportionally to the PM PI(4,5)P2 levels. Phagosomes forming in Nir2/3- edited cells had decreased overall PI(4,5)P2 levels but normal periphagosomal Ca2+ signals. Nir2/3 editing reduced the density of contractile actin rings at sites of particle capture, causing repetitive low- intensity contractile events indicative of abortive phagosome closure. We conclude that Nir proteins maintains phosphoinositide homeostasis at phagocytic cups, thereby sustaining the signals that initiate the remodeling of the actin cytoskeleton during phagocytosis.
    Keywords:  Cell signaling; Cytoskeleton; Immunity; Lipid transfer; Membrane contact sites
    DOI:  https://doi.org/10.1242/jcs.260902
  20. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221092487
    Molecular Regulations of FUNDC1 at ER-Mitochondria Contacts Under Hypoxic Stress.
    Yi Zhang, Haixia Zhuang, Hao Liu, Du Feng.
      A recent research paper published in Journal of Cell Biology by Chen and colleagues describes a novel mechanism by which the MAM (Mitochondrial-associated endoplasmic reticulum membrane) protein FUNDC1 (FUN14 domain-containing protein 1) regulates mitochondrial division through altered protein post-translational modifications under hypoxic stress. The authors found that in a hypoxic environment, the endoplasmic reticulum-localized deubiquitinating enzyme USP19 accumulates at the MAM and interacts with the enriched mitochondrial outer membrane protein FUNDC1, which subsequently induces its deubiquitination and promotes the oligomerization and activity of DRP1, and mitochondria eventually divide in the presence of DRP1. This article provides new insights into the regulation of mitochondrial dynamics by FUNDC1 under hypoxic condition.
    Keywords:  DRP1; FUNDC1; MAM; Mitochondria; USP19
    DOI:  https://doi.org/10.1177/25152564221092487
  21. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221095961
    Ca2+ Signalling is a Conserved Game of Contact.
    Hannah Casbolt, Michelangelo Campanella.
      Apicoplasts are critical for the growth of medically important parasites. It is now reported that they form contacts with the endoplasmic reticulum (ER) via two pore channels thus enabling Ca2+ trafficking. This highlights the dynamic physical association between organelles as a critical motif in Ca2+ signaling.
    DOI:  https://doi.org/10.1177/25152564221095961
  22. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221101974
    Csf1: A Putative Lipid Transport Protein Required for Homeoviscous Adaptation of the Lipidome.
    Arun T John Peter, Ngaam J Cheung, Benoît Kornmann.
      The non-vesicular transport of lipids between organelles mediated by lipid transport proteins (LTPs) is a key determinant of organelle biogenesis and function. Despite performing a vital function in organelle homeostasis, none of the LTP-encoding genes identified so far are truly essential, even in the simple genome of yeast, suggesting widespread redundancy. In line with this fact, it has been found that a number of LTPs have overlapping functions, making it challenging to assign unique roles for an individual LTP in lipid distribution. In our genetic screens under stringent conditions in which the distinct function of an LTP might become essential, we stumbled upon Csf1, a highly conserved protein with a Chorein-N motif found in other lipid transporters and unraveled a new function for Csf1 in lipid remodeling and homeoviscous adaptation of the lipidome. Here, we further speculate on the potential mechanisms of how the putative function of Csf1 in lipid transport could be intimately connected to its role in lipid remodeling across organelles.
    Keywords:  chorein-N motif; homeoviscous adaptation; lipid remodeling; lipid transport; membrane contact sites
    DOI:  https://doi.org/10.1177/25152564221101974
  23. Redox Biol. 2023 Jun 20. pii: S2213-2317(23)00189-1. [Epub ahead of print]64 102788
    Bmal1 downregulation leads to diabetic cardiomyopathy by promoting Bcl2/IP3R-mediated mitochondrial Ca2+ overload.
    Nannan Zhang, Hao Yu, Tianzi Liu, Zihao Zhou, Bin Feng, Yao Wang, Zhiyong Qian, Xiaofeng Hou, Jiangang Zou.
      Brain and muscle arnt-like protein 1 (Bmal1) is a crucial transcription factor, regulating circadian rhythm and involved in multiple heart diseases. However, it is unknown whether Bmal1 promotes diabetic cardiomyopathy (DCM) pathogenesis. The objective of this investigation was to ascertain the vital role of Bmal1 in the progression of DCM. Mice with T2D and H9c2 cardiomyoblasts exposed to high glucose and palmitic acid (HGHP) were used. Cardiomyocyte-specific knockout mouse of Bmal1 (CKB) was also generated, and cardiac Bmal1 was overexpressed in type 2 diabetes (T2D) mice using an adeno-associated virus. Bmal1 gene recombinant adenovirus was used to either knockdown or overexpress in H9c2 cardiomyoblasts. Bmal1 expression was significantly altered in diabetic mice hearts. Bmal1 downregulation in CKB and T2D mice heart accelerated cardiac hypertrophy and diastolic dysfunction, while Bmal1 overexpression ameliorated these pathological changes in DCM mice. Furthermore, DCM mice had significant mitochondrial ultrastructural defects, reactive oxygen species accumulation, and apoptosis, which could be alleviated by overexpressing Bmal1. In H9c2 cardiomyoblasts, genetic downregulation of Bmal1 or HGHP markedly decreased the binding of Bcl2 to IP3R, thus increasing Ca2+ release to mitochondria through mitochondria-associated endoplasmic reticulum membranes. Importantly, chromatin immunoprecipitation revealed Bmal1 could bind directly to the Bcl2 gene promoter region. Bmal1 overexpression augmented the Bmal1/Bcl2 binding, enhancing the inhibition of Bcl2 on IP3R activity, thus alleviating mitochondrial Ca2+ overload and subsequent cell apoptosis. These results show that Bmal1 is involved in the DCM development through Bcl2/IP3R-mediated mitochondria Ca2+ overload. Therapy targeting the circadian clock (Bmal1) can treat DCM.
    Keywords:  Bmal1; Ca(2+) overload; Diabetic cardiomyopathy; Heart failure; Mitochondrial-associated endoplasmic reticulum membranes
    DOI:  https://doi.org/10.1016/j.redox.2023.102788
  24. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211031738
    Corrigendum to "Getting in Touch is an Important Step: Control of Metabolism at Organelle Contact Sites".
      [This corrects the article DOI: 10.1177/2515256421993708.].
    DOI:  https://doi.org/10.1177/25152564211031738
  25. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221114513
    Sorting (Nexin-13) out Novel Insights into Endolysosomal Cholesterol Export.
    Albert Lu.
      Transport in and out of the endolysosomal compartment represents a key step in the regulation of cellular cholesterol homeostasis. Despite important recent advances, how LDL-derived, free cholesterol is exported from the lumen of endolysosomes to other organelles is still a matter of debate. We recently devised a CRISPR/Cas9 genome-scale strategy to uncover genes involved in the regulation of endolysosomal cholesterol homeostasis and the functionally linked phospholipid, bis(monoacylglycerol)-phosphate. This approach confirmed known genes and pathways involved in this process, and more importantly revealed previously unrecognized roles for new players, such as Sorting Nexin-13 (SNX13). Here we discuss the unexpected regulatory role of SNX13 in endolysosomal cholesterol export.
    Keywords:  cholesterol transport; endolysosomes; endoplasmic reticulum; membrane contact sites; niemann-pick disease
    DOI:  https://doi.org/10.1177/25152564221114513
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