bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024‒03‒31
eight papers selected by
Verena Kohler, Umeå University
  1. Nucleus-Mitochondria Contact Sites Are Associated With Asynthetic Fission in Zebrafish Skin.
  2. Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.
  3. Bridge-like lipid transfer protein family member 2 suppresses ciliogenesis.
  4. Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.
  5. OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion.
  6. Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.
  7. STIM2 variants regulate Orai1/TRPC1/TRPC4-mediated store-operated Ca2+ entry and mitochondrial Ca2+ homeostasis in cardiomyocytes.
  8. The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.
  1. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241239445
    Nucleus-Mitochondria Contact Sites Are Associated With Asynthetic Fission in Zebrafish Skin.
    Dhani Tracey-White, Matthew J Hayes.
      Rapid increase in body surface area of growing zebrafish larvae (Danio rario) is partially accomplished by asynthetic fission of superficial epithelial cells (SECs) of the skin. There are two cycles of this atypical form of cell division which is unaccompanied by DNA replication; resulting in cells with a variable DNA content. Here, electron microscopy of basal epithelium cells that give rise to these SECs in zebrafish larvae shows aggregation of mitochondria around the nucleus and the formation of nucleus-mitochondria membrane contact sites. Membrane aggregates appear in the lumen of the nuclear envelope at these sites of membrane contact in some cells, suggesting lipid turnover in this vicinity. As the epithelial cells mature and stratify, the mitochondria are engulfed by extensions arising from the nuclear envelope. The mitochondrial outer membrane fragments and mitochondria fuse with the nuclear envelope and parts of the endoplasmic reticulum. Other organelles, including the Golgi apparatus, progressively localize to a central region of the cell and lose their integrity. Thus, asynthetic fission is accompanied by an atypical pattern of organelle destruction and a prelude to this is the formation of nucleus-mitochondria membrane contact sites.
    Keywords:  asynthetic fission; contact site; corneocyte; danio rerio; epidermis; keratocyte; membrane contact site; nucleus–mitochondria; site of membrane contact
    DOI:  https://doi.org/10.1177/25152564241239445
  2. Elife. 2024 Mar 27. pii: RP89938. [Epub ahead of print]12
    Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.
    Kazuki Hanaoka, Kensuke Nishikawa, Atsuko Ikeda, Philipp Schlarmann, Saku Sasaki, Sotaro Fujii, Sayumi Yamashita, Aya Nakaji, Kouichi Funato.
      Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)-plasma membrane (PM) and ER-Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus-vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.
    Keywords:  S. cerevisiae; cell biology; membrane contact sites; sphingolipid; tricalbin; vacuolar morphology
    DOI:  https://doi.org/10.7554/eLife.89938
  3. Mol Biol Cell. 2024 Mar 27. mbcE24020065
    Bridge-like lipid transfer protein family member 2 suppresses ciliogenesis.
    Jan Parolek, Christopher G Burd.
      Bridge-like lipid transfer protein family member 2 (BLTP2) is an evolutionary conserved protein with unknown function(s). The absence of BLTP2 in Drosophila melanogaster results in impaired cellular secretion and larval death, while in mice (Mus musculus), it causes preweaning lethality. Structural predictions propose that BLTP2 belongs to the repeating β-groove domain-containing (also called the VPS13) protein family, forming a long tube with a hydrophobic core, suggesting that it operates as a lipid transfer protein (LTP). We establish BLTP2 as a negative regulator of ciliogenesis in RPE-1 cells based on a strong genetic interaction with WDR44, a gene that also suppresses ciliogenesis. Like WDR44, BLTP2 localizes to membrane contact sites involving the endoplasmic reticulum and the tubular endosome network in HeLa cells and that BLTP2 depletion enhanced ciliogenesis in RPE-1 cells grown in serum-containing medium, a condition where ciliogenesis is normally suppressed. This study establishes human BLTP2 as a putative lipid transfer protein acting between tubular endosomes and ER that regulates primary cilium biogenesis.
    DOI:  https://doi.org/10.1091/mbc.E24-02-0065
  4. Int J Mol Sci. 2024 Mar 11. pii: 3196. [Epub ahead of print]25(6):
    Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.
    Xi Li, Yangjun Yang, Xiaoyu Shi, Zhe Zhang, Shuzhe Ding.
      The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.
    Keywords:  calcium homeostasis; endoplasmic reticulum stress; exercise; insulin resistance; lipid homeostasis; mitochondria-associated membranes; mitochondrial quality control
    DOI:  https://doi.org/10.3390/ijms25063196
  5. Cell Rep. 2024 Mar 26. pii: S2211-1247(24)00320-6. [Epub ahead of print]43(4): 113992
    OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion.
    Styliani Panagiotou, Kia Wee Tan, Phuoc My Nguyen, Andreas Müller, Affiong Ika Oqua, Alejandra Tomas, Anna Wendt, Lena Eliasson, Anders Tengholm, Michele Solimena, Olof Idevall-Hagren.
      Insulin is packaged into secretory granules that depart the Golgi and undergo a maturation process that involves changes in the protein and lipid composition of the granules. Here, we show that insulin secretory granules form physical contacts with the endoplasmic reticulum and that the lipid exchange protein oxysterol-binding protein (OSBP) is recruited to these sites in a Ca2+-dependent manner. OSBP binding to insulin granules is positively regulated by phosphatidylinositol-4 (PI4)-kinases and negatively regulated by the PI4 phosphate (PI(4)P) phosphatase Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and small interfering RNA (siRNA)-mediated knockdown of OSBP suppress glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at endoplasmic reticulum (ER)-granule contact sites is involved in the exocytic process and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation.
    Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); OSBP; beta cell; endoplasmic reticulum; insulin; membrane contact sites; pH; phophatidylinositol 4-phosphate; secretory granule
    DOI:  https://doi.org/10.1016/j.celrep.2024.113992
  6. Eur J Pharmacol. 2024 Mar 23. pii: S0014-2999(24)00218-8. [Epub ahead of print] 176530
    Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.
    Chenyan Zhang, Bowen Liu, Jiaxing Sheng, Jia Wang, Weijie Zhu, Chen Xie, Xuan Zhou, Yuxin Zhang, Qinghai Meng, Yu Li.
      After myocardial infarction (MI), there is a notable disruption in cellular calcium ion homeostasis and mitochondrial function, which is believed to be intricately linked to endoplasmic reticulum (ER) stress. This research endeavors to elucidate the involvement of glucose regulated protein 75 (GRP75) in post-MI calcium ion homeostasis and mitochondrial function. In MI rats, symptoms of myocardial injury were accompanied by an increase in the activation of ER stress. Moreover, in oxygen-glucose deprivation (OGD)-induced cardiomyocytes, it was confirmed that inhibiting ER stress exacerbated intracellular Ca2+ disruption and cell apoptosis. Concurrently, the co-localization of GRP75 with IP3R and VDAC1 increased under ER stress in cardiomyocytes. In OGD-induced cardiomyocytes, knockdown of GRP75 not only reduced the Ca2+ levels in both the ER and mitochondria and improved the ultrastructure of cardiomyocytes, but it also increased the number of contact points between the ER and mitochondria, reducing mitochondria associated endoplasmic reticulum membrane (MAM) formation, and decreased cell apoptosis. Significantly, knockdown of GRP75 did not affect the protein expression of PERK and hypoxia-inducible factor 1α (HIF-1α). Transcriptome analysis of cardiomyocytes revealed that knockdown of GRP75 mainly influenced the molecular functions of sialyltransferase and IP3R, as well as the biosynthesis of glycosphingolipids and lactate metabolism. The complex interaction between the ER and mitochondria, driven by the GRP75 and its associated IP3R1-GRP75-VDAC1 complex, is crucial for calcium homeostasis and cardiomyocyte's adaptive response to ER stress. Modulating GRP75 could offer a strategy to regulate calcium dynamics, diminish glycolysis, and thereby mitigate cardiomyocyte apoptosis.
    Keywords:  Calcium ion homeostasis; Endoplasmic reticulum stress; GRP75; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176530
  7. Cell Calcium. 2024 Mar 19. pii: S0143-4160(24)00029-0. [Epub ahead of print]119 102871
    STIM2 variants regulate Orai1/TRPC1/TRPC4-mediated store-operated Ca2+ entry and mitochondrial Ca2+ homeostasis in cardiomyocytes.
    Rui Luo, Pauline Le Gourriérec, Fabrice Antigny, Kaveen Bedouet, Séverine Domenichini, Ana-Maria Gomez, Jean-Pierre Benitah, Jessica Sabourin.
      The stromal interaction molecules (STIMs) are the sarcoplasmic reticulum (SR) Ca2+ sensors that trigger store-operated Ca2+ entry (SOCE) in a variety of cell types. While STIM1 isoform has been the focus of the research in cardiac pathophysiology, the function of the homolog STIM2 remains unknown. Using Ca2+ imaging and patch-clamp techniques, we showed that knockdown (KD) of STIM2 by siRNAs increased SOCE and the ISOC current in neonatal rat ventricular cardiomyocytes (NRVMs). Within this cardiomyocyte model, we identified the transcript expression of Stim2.1 and Stim2.2 splice variants, with predominance for Stim2.2. Using conventional and super-resolution confocal microscopy (STED), we found that exogenous STIM2.1 and STIM2.2 formed pre-clusters with a reticular organization at rest. Following SR Ca2+ store depletion, some STIM2.1 and STIM2.2 clusters were translocated to SR-plasma membrane (PM) junctions and co-localized with Orai1. The overexpression strategy revealed that STIM2.1 suppressed Orai1-mediated SOCE and the ISOC current while STIM2.2 enhanced SOCE. STIM2.2-enhanced SOCE was also dependent on TRPC1 and TRPC4. Even if STIM2 KD or splice variants overexpression did not affect cytosolic Ca2+ cycling, we observed, using Rhod-2/AM Ca2+ imaging, that Orai1 inhibition or STIM2.1 overexpression abolished the mitochondrial Ca2+ (mCa2+) uptake, as opposed to STIM2 KD. We also found that STIM2 was present in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) by interacting with the inositol trisphosphate receptors (IP3Rs), voltage-dependent anion channel (VDAC), mitochondrial Ca2+ uniporter (MCU), and mitofusin-2 (MNF2). Our results suggested that, in NRVMs, STIM2.1 constitutes the predominant functional variant that negatively regulates Orai1-generated SOCE. It participates in the control of mCa2+ uptake capacity possibly via the STIM2-IP3Rs-VDAC-MCU and MNF2 complex.
    Keywords:  Cardiomyocytes; MAMs; Orai1; STIM2; STIM2.1; STIM2.2; Store-operated Ca(2+) entry
    DOI:  https://doi.org/10.1016/j.ceca.2024.102871
  8. Arch Toxicol. 2024 Mar 27.
    The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.
    Lei Bao, Qingping Liu, Jingyuan Wang, Lili Shi, Yaxian Pang, Yujie Niu, Rong Zhang.
      Owing to the widespread use and improper emissions of carbon black nanoparticles (CBNPs), the adverse effects of CBNPs on human health have attracted much attention. In toxicological research, carbon black is frequently utilized as a negative control because of its low toxicity and poor solubility. However, recent studies have indicated that inhalation exposure to CBNPs could be a risk factor for severe and prolonged pulmonary inflammation and fibrosis. At present, the pathogenesis of pulmonary fibrosis induced by CBNPs is still not fully elucidated, but it is known that with small particle size and large surface area, CBNPs are more easily ingested by cells, leading to organelle damage and abnormal interactions between organelles. Damaged organelle and abnormal organelles interactions lead to cell structure and function disorders, which is one of the important factors in the development and occurrence of various diseases, including pulmonary fibrosis. This review offers a comprehensive analysis of organelle structure, function, and interaction mechanisms, while also summarizing the research advancements in organelles and organelle interactions in CBNPs-induced pulmonary fibrosis.
    Keywords:  Carbon black nanoparticles; Membrane contact sites; Organelle interactions; Organelles
    DOI:  https://doi.org/10.1007/s00204-024-03719-0
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒31 at 16:01.