bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–12–15
ten papers selected by
Verena Kohler, Umeå University
  1. Studying ER-membrane contact sites in plants using the optogenetic approach: Taking the LiMETER as an example.
  2. Exploring the pathophysiological mechanisms and wet biomarkers of VPS13A disease.
  3. STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis.
  4. Store-Operated Ca2+ Entry in Fibrosis and Tissue Remodeling.
  5. Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis.
  6. The application of different biotechnologies in detecting the changes in MAM and their classic discoveries.
  7. XopM, An FFAT Motif-Containing Type III Effector Protein From Xanthomonas, Suppresses MTI Responses at the Plant Plasma Membrane.
  8. Mitochondrial Alterations in Alzheimer's Disease: Insight from the 5xFAD Mouse Model.
  9. ORP5 promotes cardiac hypertrophy by regulating the activation of mTORC1 on lysosome.
  10. Augmenter of liver regeneration (ALR) crotonylation assists in mitochondria-ER contact to alleviate hepatic steatosis.
  1. Plant J. 2024 Dec 10.
    Studying ER-membrane contact sites in plants using the optogenetic approach: Taking the LiMETER as an example.
    Yifan Li, Charlotte Pain, Xuan Cui, Menghan Li, Tong Zhang, Jiejie Li, Verena Kriechbaumer, Pengwei Wang.
      The endoplasmic reticulum (ER) links to multiple organelles through membrane contact sites (MCS), which play critical roles in signal transduction, cell homeostasis and stress response. However, studying the behaviour and functions of MCS in plants is still challenging, partially due to the lack of site-specific markers. Here, we used an optogenetic reporter, LiMETER (Light-inducible Membrane-Tethered cortical ER), to study the structure and dynamics of ER-PM contact sites (EPCS) in plants. Upon blue light activation, LiMETER is recruited to the EPCS rapidly, while this process is reversible when blue light is turned off. Compared with other EPCS reporters, LiMETER specifically and reversibly labels the contact sites, causing little side-effects on the ER structure and plant development. With its help, we re-examined the formation of ER-PM connections induced by cell-intrinsic factors or extracellular stimuli. We found that EPCSs are preferably localised at ER tubules and the edge of ER cisternae, and their number increased significantly under abiotic stress conditions. The abundance of ER and PM interaction is also developmental dependent, suggesting a direct link between ER-PM interaction, ER function and cell homeostasis. Taken together, we showed that LiMETER is an improved marker for functional and microscopical studies of ER-PM interaction, demonstrating the effectiveness of optogenetic tools in future research.
    Keywords:  Arabidopsis thaliana; ER morphology; ER stress response; ER‐PM contact sites; Nicotiana benthamiana; endoplasmic reticulum; light microscopy; optogenetics; technical advance
    DOI:  https://doi.org/10.1111/tpj.17191
  2. Front Neurol. 2024 ;15 1482936
    Exploring the pathophysiological mechanisms and wet biomarkers of VPS13A disease.
    Jingqi Lin, Hongmei Meng, Nilupaer Shafeng, Jiaai Li, Huaiyu Sun, Xi Yang, Zhiqing Chen, Shuai Hou.
      VPS13A disease (also known as Chorea-Acanthocytosis, ChAc) is a representative subtype of the neuroacanthocytosis (NA) syndromes, characterized by neurodegeneration in the central nervous system and acanthocytosis in peripheral blood. It is a rare autosomal recessive genetic disorder caused by loss-of-function variants in the VPS13A gene, which is currently the only known pathogenic gene for ChAc. VPS13A protein is a member of novel bridge-like lipid transfer proteins family located at membrane contact sites, forming direct channels for lipid transport. The specific mechanism underlying how the loss of VPS13A function leads to the hematological and neurological phenotypes of the disease remains unclear. Here we present a review of recent studies on VPS13A protein and ChAc, focusing on the potential role of the VPS13A protein in pathophysiology of ChAc and also review the known and potential wet biomarkers of ChAc to enhance our comprehension of this rare disease.
    Keywords:  VPS13A; VPS13A disease; chorea-acanthocytosis; chorein; neuroacanthocytosis
    DOI:  https://doi.org/10.3389/fneur.2024.1482936
  3. Cell Calcium. 2024 Nov 29. pii: S0143-4160(24)00138-6. [Epub ahead of print]125 102980
    STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis.
    Maria Livia Sassano, Robbe Van Gorp, Geert Bultynck, Patrizia Agostinis.
      The endoplasmic reticulum (ER) controls intracellular Ca2+ dynamics. Depletion of ER Ca2+ stores results in short-term activation of store-operated Ca2+ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.
    Keywords:  IP3 receptors; IRE1; STIM1; Store-operated calcium entry; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ceca.2024.102980
  4. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241291374
    Store-Operated Ca2+ Entry in Fibrosis and Tissue Remodeling.
    Ahmed Emam Abdelnaby, Mohamed Trebak.
      Fibrosis is a pathological condition characterized by excessive tissue deposition of extracellular matrix (ECM) components, leading to scarring and impaired function across multiple organ systems. This complex process is mediated by a dynamic interplay between cell types, including myofibroblasts, fibroblasts, immune cells, epithelial cells, and endothelial cells, each contributing distinctively through various signaling pathways. Critical to the regulatory mechanisms involved in fibrosis is store-operated calcium entry (SOCE), a calcium entry pathway into the cytosol active at the endoplasmic reticulum-plasma membrane contact sites and common to all cells. This review addresses the multifactorial nature of fibrosis with a focus on the pivotal roles of different cell types. We highlight the essential functions of myofibroblasts in ECM production, the transformation of fibroblasts, and the participation of immune cells in modulating the fibrotic landscape. We emphasize the contributions of SOCE in these different cell types to fibrosis, by exploring the involvement of SOCE in cellular functions such as proliferation, migration, secretion, and inflammatory responses. The examination of the cellular and molecular mechanisms of fibrosis and the role of SOCE in these mechanisms offers the potential of targeting SOCE as a therapeutic strategy for mitigating or reversing fibrosis.
    Keywords:  Orai1; calcium release activated channel (CRAC) (ICRAC); calcium signaling; fibrosis; stromal-interaction molecule (STIM); tissue remodeling
    DOI:  https://doi.org/10.1177/25152564241291374
  5. Mov Disord. 2024 Dec 12.
    Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis.
    Kevin Peikert, Adrian Spranger, Gabriel Miltenberger-Miltenyi, Hannes Glaß, Björn Falkenburger, Christian Klose, Donatienne Tyteca, Andreas Hermann.
       BACKGROUND: VPS13A disease is an ultra-rare disorder caused by loss of function mutations in VPS13A characterized by striatal degeneration and by red blood cell (RBC) acanthocytosis. VPS13A is a bridge-like protein mediating lipid transfer at membrane contact sites.
    OBJECTIVES: To assess the lipid composition of patient-derived RBCs.
    METHODS: RBCs collected from 5 VPS13A disease patients and 12 control subjects were analyzed by mass spectrometry (lipidomics).
    RESULTS: While we found no significant differences in the overall lipid class level, alterations in certain species were detected: phosphatidylethanolamine species with both longer chain length and higher unsaturation were increased in VPS13A disease samples. Specific ceramide, phosphatidylcholine, and sphingomyelin species were also altered.
    CONCLUSIONS: The presented alterations of particular lipid species in RBCs in VPS13A disease may contribute to (1) the understanding of acanthocyte formation, and (2) future biomarker identification. Lipid distribution seems to play a key role in the pathophysiology of VPS13A disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    DOI:  https://doi.org/10.1002/mds.30086
  6. Anal Biochem. 2024 Dec 06. pii: S0003-2697(24)00288-4. [Epub ahead of print]698 115744
    The application of different biotechnologies in detecting the changes in MAM and their classic discoveries.
    Shuangshuang Zhang, Yingchun Shao, Mengzhu Su, Yuerong Hao, Yang Yuan, Dongming Xing.
      Mitochondria-associated membrane (MAM) has been studied as a novel target for explaining the mechanisms underlying the changes in cellular function and the process of multiple diseases. This structure is a complex of proteins, it tethers mitochondria to the endoplasmic/sarcoplasmic reticulum (ER/SR) and mediates the crosstalk of ions, lipids and metabolites between the two organelles. Different component proteins play distinctive ways in influencing the structure of MAM or the cellular signal transduction. Mitochondria and ER are the hubs of cellular bioenergetics and protein homeostasis respectively, MAM was supposed to play both physiological and pathological roles in regulating the function of either the two organelles and cells. The mitochondria-associated membrane is a highly dynamic structure and could be disrupted or remodelled within several minutes. Up to now, not all component proteins of the MAM complex have been revealed. Several biochemical and imaging approaches have been used to measure the changes in the structure or the number of MAMs, but they come with their issues. For distinct research aims, particular techniques were used based on their applicabilities, the research platforms and technical defects. This review briefly summarized the current biotechnologies for detecting MAM, and analyzed their limitations, aiming to assist further research in selecting appropriate methods based on actual situations.
    Keywords:  Co-immunofluorescence; Electron microscopy; Endoplasmic reticulum; Mitochondria-associated membrane; Proximity ligation assay
    DOI:  https://doi.org/10.1016/j.ab.2024.115744
  7. Mol Plant Pathol. 2024 Dec;25(12): e70038
    XopM, An FFAT Motif-Containing Type III Effector Protein From Xanthomonas, Suppresses MTI Responses at the Plant Plasma Membrane.
    Charlotte Brinkmann, Jennifer Bortlik, Margot Raffeiner, Manuel González-Fuente, Linus F Börnke, Suayib Üstün, Frederik Börnke.
      Many gram-negative pathogenic bacteria use type III effector proteins (T3Es) as essential virulence factors to suppress host immunity and to cause disease. However, in many cases the molecular function of T3Es remains unknown. The plant pathogen Xanthomonas campestris pv. vesicatoria (Xcv) is the causal agent of bacterial spot disease on tomato and pepper plants and is known to translocate around 36 T3Es into its host cell, which collectively suppress plant defence and promote infection. XopM is an Xcv core T3E with unknown function that has no similarity to any other known protein. We found that XopM interacts with vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) in an isoform-specific manner. The endoplasmic reticulum (ER) integral membrane protein VAP is a common component of membrane contact sites involved in both tethering and lipid transfer by binding directly to proteins containing an FFAT (two phenylalanines [FF] in an acidic tract [AT]) motif. Sequence analyses revealed that XopM displays two FFAT motifs that cooperatively mediated the interaction of XopM with VAP. When expressed in plants, XopM supported growth of a nonpathogenic bacterial strain and dampened the production of reactive oxygen species, indicating its ability to suppress plant immunity. Further analyses revealed that the interaction with VAP and the ability to suppress microbe-associated molecular pattern-triggered immunity (MTI) are structurally and functionally separable, although XopM requires localisation to the host membrane system for full MTI suppression activity. We discuss a working model in which XopM uses FFAT motifs to target the membrane to interfere with early MTI responses.
    Keywords:   Xanthomonas ; FFAT motif; VAP proteins; XopM; plant defence; type III effector
    DOI:  https://doi.org/10.1111/mpp.70038
  8. Mol Neurobiol. 2024 Dec 11.
    Mitochondrial Alterations in Alzheimer's Disease: Insight from the 5xFAD Mouse Model.
    Elif Nedret Keskinoz, Musa Celik, Ezgi Sila Toklucu, Kerem Birisik, Alev Erisir, Devrim Oz-Arslan.
      Mitochondrial dysfunction is increasingly recognized as a key factor in Alzheimer's disease (AD) pathogenesis, but the precise relationship between mitochondrial dynamics and proteinopathies in AD remains unclear. This study investigates the role of mitochondrial dynamics and function in the hippocampal tissue and peripheral blood mononuclear cells (PBMCs) of 5xFAD transgenic mice, as a model of AD. The levels of mitochondrial fusion proteins OPA1 and MFN2 and fission proteins DRP1 and phospho-DRP1 (S616) at 3, 6, and 9 months of age were assessed. Western blot analysis revealed significantly lower levels of OPA1 and MFN2 in the hippocampus of 6- and 9-month-old transgenic (TG) 5xFAD mice compared to controls (CTR), while DRP1 and pDRP1 levels were increased in 9-month-old TG mice. Additionally, MFN2 were decreased in the PBMCs of 9-month-old TG mice, indicating systemic mitochondrial alterations. Ultrastructural analysis of hippocampal tissues showed substantial alterations in mitochondrial morphology, including abnormalities in size and shape, a preponderance of teardrop-shaped mitochondria, and alterations in the somatic mitochondria-ER complex. Notably, mitochondria-associated ER contact sites were more distant in TG mice, suggesting functional impairments. Flow cytometric measurements demonstrated decreased mitochondrial membrane potential and mass, along with increased superoxide production, in the PBMCs of TG mice, particularly at 9 months, highlighting compromised mitochondrial function. Levels of key mitochondrial proteins including VDAC, TOM2O, and mitophagy-related protein PINK1 levels altered in both central and peripheral tissue of TG mice. These findings suggest that mitochondrial dysfunction and altered dynamics are early events in AD development in 5xFAD mice, manifesting in both central and peripheral tissues, and support the notion that mitochondrial abnormalities are an integral component of AD pathology. These insights might lead to the development of targeted therapies that modulate mitochondrial dynamics and function to mitigate AD progression.
    Keywords:  Electron microscopy; Flow cytometry; MERCs; Mitochondrial dynamics; Western blot
    DOI:  https://doi.org/10.1007/s12035-024-04632-4
  9. J Adv Res. 2024 Dec 10. pii: S2090-1232(24)00591-5. [Epub ahead of print]
    ORP5 promotes cardiac hypertrophy by regulating the activation of mTORC1 on lysosome.
    Di Zhao, Ran Xu, Yufei Zhou, Jiaying Wu, Xiaoxue Zhang, Hong Lin, Jienan Wang, Zhiwen Ding, Yunzeng Zou.
       INTRODUCTION: Oxysterol binding protein (OSBP)-related protein 5 (ORP5) mainly functions as a lipid transfer protein at membrane contact sites (MCS). ORP5 facilitates cell proliferation through the activation of mTORC1 signaling. While the pro-hypertrophic effects of mTORC1 are well-documented, the specific role of ORP5 in the context of pathological cardiac hypertrophy remains inadequately understood.
    METHODS: To investigate the role of ORP5 in pathological cardiac hypertrophy, AAV9-treated mice and neonatal rat ventricular myocytes (NRVMs) were utilized. Cardiac function, morphology, and mTORC1 signaling alterations induced by pro-hypertrophic stimuli were assessed in both myocardium and NRVMs. Additionally, a range of molecular techniques were employed to elucidate the regulatory mechanisms of ORP5 on mTORC1 in hypertrophied hearts.
    RESULTS: Increased expression of ORP5 was observed in the hearts of patients with hypertrophic cardiomyopathy (HCM), in mice subjected to transverse aortic constriction (TAC), and in NRVMs treated with angiotensin II (AngII). We found that ORP5 binds to mTOR in cardiomyocytes. Upon exposure to TAC surgery, ORP5-deficient hearts exhibited enhanced cardiac function, reduced cardiomyocyte hypertrophy, and diminished collagen deposition than wild type. Conversely, overexpression of ORP5 significantly aggravated hypertrophic responses in both hearts and NRVMs. Notably, the promotion of cardiac hypertrophy induced by ORP5 overexpression was reversed by rapamycin, an inhibitor of mTORC1. Mechanistically, our study elucidated that the ORD domain of ORP5 interacts with mTORC1, facilitating its translocation to the outer membrane of the lysosome for subsequent activation. This activation triggers the downstream signaling pathways involving S6K1 and 4E-BP1, which initiate protein synthesis, thereby promoting pathological cardiac hypertrophy.
    CONCLUSIONS: Our findings provide the inaugural evidence that ORP5 facilitates pathological ventricular hypertrophy through the translocation of mTORC1 to the lysosome for subsequent activation. Consequently, ORP5 has the potential to serve as a diagnostic biomarker or therapeutic target for pathological cardiac hypertrophy in the future.
    Keywords:  Heart failure; Lysosome; ORP5; Pathological cardiac hypertrophy; mTORC1
    DOI:  https://doi.org/10.1016/j.jare.2024.12.014
  10. Cell Mol Gastroenterol Hepatol. 2024 Dec 06. pii: S2352-345X(24)00191-7. [Epub ahead of print] 101436
    Augmenter of liver regeneration (ALR) crotonylation assists in mitochondria-ER contact to alleviate hepatic steatosis.
    Xiao-Lin Wang, Jia-Hao He, Ping Xie, Yuan Wu, Ling-Yue Dong, Wei An.
       BACKGROUND & AIMS: Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people's health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown.
    METHODS: Steatotic liver samples from human and western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in in-vivo and in-vitro experiments.
    RESULTS: Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of MASLD patients and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr which takes place at lysine 78 (K78). The decrease of ALR crotonylation, might be related to the imbalance between HADC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis.
    CONCLUSIONS: The insufficient of ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.
    Keywords:  Augmenter of liver regeneration; Crotonylation; Metabolic dysfunction-associated steatotic liver disease; Mitochondria-associated membrane
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.101436
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