bims-mecosi 2022-02-27 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2022‒02‒27
seven papers selected by
Verena Kohler

Enforced tethering elongates the cortical endoplasmic reticulum and limits store-operated calcium entry.
Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.
Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging.
The STIM1 Phosphorylation Saga.
Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.
Curcumin Inhibits Cell Damage and Apoptosis Caused by Thapsigargin-Induced Endoplasmic Reticulum Stress Involving the Recovery of Mitochondrial Function Mediated by Mitofusin-2.
The Passage of H2O2 from Chloroplasts to Their Associated Nucleus during Retrograde Signalling: Reflections on the Role of the Nuclear Envelope.

J Cell Sci. 2022 Feb 22. pii: jcs.259313. [Epub ahead of print]

Enforced tethering elongates the cortical endoplasmic reticulum and limits store-operated calcium entry.

Christopher Henry, Amado Carreras-Sureda, Nicolas Demaurex.

  Recruitment of STIM proteins to cortical ER (cER) domains forming membrane contact sites (MCS) mediate the store-operated Ca2+ entry (SOCE) pathway essential for human immunity. The cER is dynamically regulated by STIM and tethering proteins during SOCE, but the ultrastructural rearrangement and functional consequences of cER remodelling are unknown. Here, we express natural (E-Syt1/2) and artificial (MAPPER-S/L) protein tethers in HEK-293T cells and correlate the changes in cER length and gap distance measured by electron microscopy with ionic fluxes. Native cER cisternae extended during store depletion and remained elongated at constant ER-PM gap distance during subsequent Ca2+ elevations. Tethering proteins enhanced store-dependent cER expansion, anchoring the enlarged cER at tether-specific gap distances of 12-15nm (E-Syts) and 5-9nm (MAPPERs). Cells with artificially extended cER had reduced SOCE and reduced agonist-induced Ca2+ release. SOCE remained modulated by calmodulin and exhibited enhanced Ca2+-dependent inhibition. We propose that cER expansion mediated by ER-PM tethering at a close distance negatively regulates SOCE by confining STIM-ORAI complexes to the periphery of enlarged cER sheets, a process that might participate in the termination of store-operated Ca2+ entry.

Keywords:  Calcium signaling; Electron microscopy; Innate immunity; Ion channels; Membrane contact sites; Muscle physiology

DOI:  https://doi.org/10.1242/jcs.259313
EMBO J. 2022 Feb 25. e108272

Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Jorida Çoku, David M Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, Gyorgy Hajnoczky, Michael D Hogarty.

  Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.

Keywords:  ceramides; inter-organelle contacts; mitochondria-associated membranes; multidrug resistance; sphingolipids

DOI:  https://doi.org/10.15252/embj.2021108272
Antioxidants (Basel). 2022 Jan 19. pii: 192. [Epub ahead of print]11(2):

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging.

Jinoh Kim, Hua Bai.

  Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as "peroxisomal stress response pathways". Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research.

Keywords:  ER stress; acetyl-CoA; apoptosis; mitochondrial dysfunction; peroxisome; pexophagy; plasmalogen; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox11020192
Cell Calcium. 2022 Feb 16. pii: S0143-4160(22)00026-4. [Epub ahead of print]103 102551

The STIM1 Phosphorylation Saga.

Fang Yu, Khaled Machaca.

  Store-operated Ca2+ entry (SOCE) is a Ca2+ influx pathway present in practically every cell type in metazoans and mediates a variety of physiological functions. Defects in SOCE are associated with immunodeficiencies and defects in skeletal muscle development and function. The molecular machinery underpinning SOCE can be complex and cell type specific, however the minimal functional SOCE unit consists of the endoplasmic reticulum (ER) Ca2+ sensor STIM1 and the plasma membrane (PM) Ca2+-selective channel Orai1. STIM1 localizes to ER-PM contact sites (CS) following store depletion, where it recruits and gates Orai1. STIM1 is a phosphoprotein that is hyper-phosphorylated during cell division. STIM1 phosphorylation has been implicated in several functions, including modulation of cellular metabolism, SOCE inactivation during M-phase, ER segregation during mitosis, modulation of SOCE levels, and cell migration. However, the role of STIM1 phosphorylation in the majority of these processes is controversial bringing into question the physiological function of STIM1 phosphorylation, if any. Here we review the role and modulation of STIM1 phosphorylation under various conditions and argue that except for the modulation of energy metabolism, the physiological function of STIM1 phosphorylation remains unclear.

Keywords:  AMPK; Cdk1; Cell migration; ERK/MAPK; Endoplasmic Reticulum; Meiosis; Mitosis; Phosphorylation; STIM1; Serine/threonine; Store operated Ca entry; Tyrosine; oocyte

DOI:  https://doi.org/10.1016/j.ceca.2022.102551
Cells. 2022 Feb 15. pii: 675. [Epub ahead of print]11(4):

Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.

Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Francesco P Damiano, Cecilia Bucci, Emanuele Marzetti.

  Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.

Keywords:  exosomes; extracellular vesicles; inflamm-aging; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles; mitochondrial-lysosomal axis; mitophagy; oxidative stress; senescence

DOI:  https://doi.org/10.3390/cells11040675
Neurotox Res. 2022 Feb 22.

Curcumin Inhibits Cell Damage and Apoptosis Caused by Thapsigargin-Induced Endoplasmic Reticulum Stress Involving the Recovery of Mitochondrial Function Mediated by Mitofusin-2.

He-Yan Zhou, Yu-Ying Sun, Ping Chang, Han-Chang Huang.

  Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been suggested to relate with the pathology of Alzheimer's disease (AD). However, their cross-talk is needed to investigate further. Mitofusin-2 (Mfn2) is a member of mitochondria-associated membrane (MAM), which connects endoplasmic reticulum (ER) and mitochondria. This study investigated the protective effect of curcumin on thapsigargin (TG)-induced ERS and cell apoptosis and the role of Mfn2 on mitochondrial dysfunction. The cell viability of SH-SY5Y cells was decreased and cell damage and apoptosis were increased in a concentration-dependent manner when cells were treated with TG. TG upregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. Curcumin attenuated TG-induced damage on cell viability and apoptosis and downregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. TG caused the increases in intracellular reactive oxygen species (ROS) and in the protein levels of pSer40-Nrf2 and hemoglobin oxygenase 1 (HO-1). Curcumin decreased the TG-induced intracellular ROS but did not alter the protein levels of pSer40-Nrf2 and HO-1. TG resulted in the upregulation on Mfn2 expression and mitochondrial spare respiratory capacity but the downregulation on mitochondrial basal respiration and ATP production. Curcumin attenuated the TG-induced Mfn2 expression and mitochondrial stress. When Mfn2 was silenced by shRNA interference, curcumin failed to recovery the TG-damaged mitochondrial function. In general, the TG-induced ERS trigged mitochondrial dysfunction and cell apoptosis. Curcumin attenuates TG-induced ERS and the cell damage and apoptosis. Mfn2 is required for curcumin's protection against the TG-induced damage on mitochondrial functions.

Keywords:  Curcumin; Endoplasmic reticulum stress (ERS); Mitochondrial dysfunction; Mitofusin-2 (Mfn2); SH-SY5Y cells; Thapsigargin

DOI:  https://doi.org/10.1007/s12640-022-00481-y
Plants (Basel). 2022 Feb 19. pii: 552. [Epub ahead of print]11(4):

The Passage of H2O2 from Chloroplasts to Their Associated Nucleus during Retrograde Signalling: Reflections on the Role of the Nuclear Envelope.

Emily Breeze, Philip M Mullineaux.

  The response of chloroplasts to adverse environmental cues, principally increases in light intensity, stimulates chloroplast-to-nucleus retrograde signalling, which leads to the induction of immediate protective responses and longer-term acclimation. Hydrogen peroxide (H2O2), generated during photosynthesis, is proposed to both initiate and transduce a retrograde signal in response to photoinhibitory light intensities. Signalling specificity achieved by chloroplast-sourced H2O2 for signal transduction may be dependent upon the oft-observed close association of a proportion of these organelles with the nucleus. In this review, we consider more precisely the nature of the close association between a chloroplast appressed to the nucleus and the requirement for H2O2 to cross both the double membranes of the chloroplast and nuclear envelopes. Of particular relevance is that the endoplasmic reticulum (ER) has close physical contact with chloroplasts and is contiguous with the nuclear envelope. Therefore, the perinuclear space, which transducing H2O2 molecules would have to cross, may have an oxidising environment the same as the ER lumen. Based on studies in animal cells, the ER lumen may be a significant source of H2O2 in plant cells arising from the oxidative folding of proteins. If this is the case, then there is potential for the ER lumen/perinuclear space to be an important location to modify chloroplast-to-nucleus H2O2 signal transduction and thereby introduce modulation of it by additional different environmental cues. These would include for example, heat stress and pathogen infection, which induce the unfolded protein response characterised by an increased H2O2 level in the ER lumen.

Keywords:  aquaporins; chloroplasts; cytoskeleton; endoplasmic reticulum; environmental stress; hydrogen peroxide; membrane contact sites; nuclear envelope; nucleus; peri-nuclear space; retrograde signalling

DOI:  https://doi.org/10.3390/plants11040552