bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022‒04‒03
eight papers selected by
Verena Kohler
  1. Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.
  2. Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
  3. Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
  4. SEED LIPID DROPLET PROTEIN1, SEED LIPID DROPLET PROTEIN2 and LIPID DROPLET PLASMA MEMBRANE ADAPTOR mediate lipid droplet-plasma membrane tethering.
  5. ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.
  6. Structural and biochemical insights into lipid transport by VPS13 proteins.
  7. Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca2+ Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum.
  8. Activation of endoplasmic reticulum-mitochondria coupling drives copper-induced autophagy in duck renal tubular epithelial cells.
  1. J Hepatol. 2022 Mar 28. pii: S0168-8278(22)00185-4. [Epub ahead of print]
    Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.
    Agathe Beaulant, Maya Dia, Bruno Pillot, Marie-Agnes Chauvin, Jingwei Ji-Cao, Christine Durand, Nadia Bendridi, Stephanie Chanon, Aurelie Vieille-Marchiset, Claire Crola Da Silva, Stéphanie Patouraux, Rodolphe Anty, Antonio Iannelli, Albert Tran, Philippe Gual, Hubert Vidal, Ludovic Gomez, Melanie Paillard, Jennifer Rieusset.
      BACKGROUND & AIMS: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions. Up to now, it is not clear if MAM miscommunication could have a causal role in hepatic insulin resistance and steatosis. We therefore aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment.METHODS: We analyzed hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice in a time-dependent and reversible manner, and investigated causality in hepatic metabolic alterations by expressing a specific organelle spacer or linker in mouse liver, using adenovirus.
    RESULTS: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in diet-induced obese mice. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type-2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index.
    CONCLUSIONS: ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could contribute to restoring metabolic homeostasis.
    LAY SUMMARY: The literature suggests that interactions between endoplasmic reticulum (ER) and mitochondria could play a dual role in hepatic insulin resistance and steatosis during chronic obesity. The present study reappraised time-dependent regulation of hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice and their causal role in hepatic insulin resistance and steatosis. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be improved by nutritional strategies.
    Keywords:  calcium signaling; hepatic insulin resistance; hepatic steatosis; lipid oxidation; mitochondria oxidative metabolism; mitochondria-associated membranes
    DOI:  https://doi.org/10.1016/j.jhep.2022.03.017
  2. Mol Metab. 2022 Mar 25. pii: S2212-8778(22)00050-3. [Epub ahead of print] 101481
    Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Effective communication among these systems is essential to cellular health and function, whereas disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.
    Keywords:  Contact sites; Lysosome; Metabolism; Mitochondria; Transporters; mTORC1
    DOI:  https://doi.org/10.1016/j.molmet.2022.101481
  3. Biochem Biophys Res Commun. 2022 Mar 17. pii: S0006-291X(22)00419-3. [Epub ahead of print]606 61-67
    Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
    Leandro Henrique de Paula Assis, Gabriel de Gabriel Dorighello, Helena Coutinho Franco de Oliveira.
      Macrophages play a role in host defense, tissue remodeling and inflammation. Different inflammatory stimuli drive macrophage phenotypes and responses. In this study we investigated the relationship between macrophages immune phenotype and mitochondrial bioenergetics, cell redox state and endoplasmic reticulum (ER)-mitochondria interaction. Bacterial lipopolysaccharide (LPS) and interferon-γ (IFNγ) pro-inflammatory stimuli decreased oxidative metabolism (basal, phosphorylating and maximal conditions) and increased baseline glycolysis (117%) and glycolytic capacity (43%) in THP-1 macrophages. In contrast, interleukin-4 (IL4) and interleukin-13 (IL13) anti-inflammatory stimuli increased the oxygen consumption rates in baseline conditions (21%) and associated with ATP production (19%). LPS + IFNγ stimuli reduced superoxide anion levels by accelerating its conversion into hydrogen peroxide (H2O2) while IL4+IL13 decreased H2O2 release rates. The source of these oxidants was extra-mitochondrial and associated with increased NOX2 and SOD1 gene expression. LPS + IFNγ stimuli decreased ER-mitochondria contact sites as measured by IP3R1-VDAC1 interaction (34%) and markedly upregulated genes involved in mitochondrial fusion (9-10 fold, MFN1 and 2) and fission (∼7 fold, DRP1 and FIS1). Conversely, IL4+IL13 stimuli did not altered ER-mitochondria interactions nor MFN1 and 2 expression. Together, these results unveil ER-mitochondria interaction pattern as a novel feature of macrophage immunological, metabolic and redox profiles.
    Keywords:  Endoplasmic reticulum-mitochondria interaction; Macrophage; Mitochondrial respiration; Oxidants production
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.086
  4. Plant Cell. 2022 Mar 28. pii: koac095. [Epub ahead of print]
    SEED LIPID DROPLET PROTEIN1, SEED LIPID DROPLET PROTEIN2 and LIPID DROPLET PLASMA MEMBRANE ADAPTOR mediate lipid droplet-plasma membrane tethering.
    Hannah Elisa Krawczyk, Siqi Sun, Nathan M Doner, Qiqi Yan, Magdiel Sheng Satha Lim, Patricia Scholz, Philipp William Niemeyer, Kerstin Schmitt, Oliver Valerius, Roman Pleskot, Stefan Hillmer, Gerhard H Braus, Marcel Wiermer, Robert T Mullen, Till Ischebeck.
      Membrane contact sites (MCSs) are inter-organellar connections that allow for the direct exchange of molecules, such as lipids or Ca2+ between organelles, but can also serve to tether organelles at specific locations within cells. Here we identified and characterised three proteins of Arabidopsis thaliana that form a lipid droplet (LD)-plasma membrane (PM) tethering complex in plant cells, namely LD-localised SEED LD PROTEIN (SLDP) 1 and SLDP2 and PM-localised LD-PLASMA MEMBRANE ADAPTOR (LIPA). Using proteomics and different protein-protein interaction assays, we show that both SLDPs associate with LIPA. Disruption of either SLDP1 and SLDP2 expression, or that of LIPA, leads to an aberrant clustering of LDs in Arabidopsis seedlings. Ectopic co-expression of one of the SLDPs with LIPA is sufficient to reconstitute LD-PM tethering in Nicotiana tabacum pollen tubes, a cell type characterised by dynamically moving LDs in the cytosolic streaming. Further, confocal laser scanning microscopy revealed both SLDP2.1 and LIPA to be enriched at LD-PM contact sites in seedlings. These and other results suggest that SLDP and LIPA interact to form a tethering complex that anchors a subset of LDs to the PM during post-germinative seedling growth in Arabidopsis.
    DOI:  https://doi.org/10.1093/plcell/koac095
  5. Cell Mol Life Sci. 2022 Mar 28. 79(4): 213
    ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.
    Ana Catarina Pereira, Jessica De Pascale, Rosa Resende, Susana Cardoso, Isabel Ferreira, Bruno Miguel Neves, Mylène A Carrascal, Mónica Zuzarte, Nuno Madeira, Sofia Morais, António Macedo, Anália do Carmo, Paula I Moreira, Maria Teresa Cruz, Cláudia F Pereira.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1β secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.
    Keywords:  Bipolar disorder (BD); Calcium; Endoplasmic reticulum (ER) stress; Mitochondria; Sterile inflammation; Unfolded protein response
    DOI:  https://doi.org/10.1007/s00018-022-04211-7
  6. J Cell Biol. 2022 Jun 06. pii: e202202030. [Epub ahead of print]221(5):
    Structural and biochemical insights into lipid transport by VPS13 proteins.
    Jyoti Adlakha, Zhouping Hong, PeiQi Li, Karin M Reinisch.
      VPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids to move directionally and in bulk between organellar membranes. VPS13s are anchored between membranes via interactions with receptors, including both peripheral and integral membrane proteins. Here we present the crystal structure of VPS13s adaptor binding domain (VAB) complexed with a Pro-X-Pro peptide recognition motif present in one such receptor, the integral membrane protein Mcp1p, and show biochemically that other Pro-X-Pro motifs bind the VAB in the same site. We further demonstrate that Mcp1p and another integral membrane protein that interacts directly with human VPS13A, XK, are scramblases. This finding supports an emerging paradigm of a partnership between bulk lipid transport proteins and scramblases. Scramblases can re-equilibrate lipids between membrane leaflets as lipids are removed from or inserted into the cytosolic leaflet of donor and acceptor organelles, respectively, in the course of protein-mediated transport.
    DOI:  https://doi.org/10.1083/jcb.202202030
  7. Biochemistry. 2022 Apr 01.
    Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca2+ Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum.
    Kenta Yokoi, Kohei Yamaguchi, Masakazu Umezawa, Koji Tsuchiya, Shin Aoki.
      We previously reported that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) 4 functionalized with a cationic KKKGG peptide unit on the 2-phenylpyridine ligand induces paraptosis, a relatively newly found programmed cell death, in cancer cells (Jurkat cells) via the direct transport of calcium (Ca2+) from the endoplasmic reticulum (ER) to mitochondria. Here, we describe that CGP37157, an inhibitor of a mitochondrial sodium (Na+)/Ca2+ exchanger, induces paraptosis in Jurkat cells via intracellular pathways similar to those induced by 4. The findings allow us to suggest that the induction of paraptosis by 4 and CGP37157 is associated with membrane fusion between mitochondria and the ER, subsequent Ca2+ influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential (ΔΨm). On the contrary, celastrol, a naturally occurring triterpenoid that had been reported as a paraptosis inducer in cancer cells, negligibly induces mitochondria-ER membrane fusion. Consequently, we conclude that the paraptosis induced by 4 and CGP37157 (termed paraptosis II herein) proceeds via a signaling pathway different from that of the previously known paraptosis induced by celastrol, a process that negligibly involves membrane fusion between mitochondria and the ER (termed paraptosis I herein).
    DOI:  https://doi.org/10.1021/acs.biochem.2c00061
  8. Ecotoxicol Environ Saf. 2022 Mar 24. pii: S0147-6513(22)00278-0. [Epub ahead of print]235 113438
    Activation of endoplasmic reticulum-mitochondria coupling drives copper-induced autophagy in duck renal tubular epithelial cells.
    Xiaoyu Wang, Huabin Cao, Yukun Fang, He Bai, Jing Chen, Chenghong Xing, Yu Zhuang, Xiaoquan Guo, Guoliang Hu, Fan Yang.
      Copper (Cu) as a transition metal can be toxic to public and ecosystem health at high level, but the specific mechanism of Cu-evoked nephrotoxicity remains elusive. Here, we first revealed the crosstalk between mitofusin2 (Mfn2)-dependent mitochondria-associated endoplasmic reticulum membrane (MAM) dynamics and autophagy in duck renal tubular epithelial cells under Cu exposure. Primary duck renal tubular epithelial cells were treated with 100 and 200 μM Cu sulfate for 12 h and exposed to lentivirus to deliver mitofusin2 (Mfn2). We found that excessive Cu disrupted MAM integrity, decreased the mitochondrial calcium level, co-localization of IP3R and VDAC1, the mRNA levels of PACS2, Mfn2, IP3R and MCU, and Mfn2 and VDAC1 protein levels, causing MAM dysfunction. Furthermore, Mfn2 overexpression ameliorated Cu-induced MAM dysfunction, and increased Cu-evoked autophagy in duck renal tubular epithelial cells accompanied with the elevation of autophagosomes number, ROS level, LC3 puncta, Atg5 and LC3B mRNA levels, and Beclin1, Atg14, LC3BII/LC3BI protein levels. Accordingly, our data proved that excessive Cu could trigger MAM dysfunction and autophagy in duck renal tubular epithelial cells, and Cu-induced autophagy could be activated through Mfn2-dependent MAM, providing evidence on the toxicological exploration mechanisms of Cu.
    Keywords:  Autophagy; Copper; Kidney; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitofusin2
    DOI:  https://doi.org/10.1016/j.ecoenv.2022.113438
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