bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023–02–26
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Amino acid sensing and lysosomal signaling complexes.
  2. The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy.
  3. Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts.
  4. Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming.
  5. Membrane damage and repair: a thin line between life and death.
  6. Ubiquitin and its relatives as wizards of the endolysosomal system.
  7. Lysosomes targeting pH activable imaging-guided photodynamic agents.
  1. Curr Opin Struct Biol. 2023 Feb 16. pii: S0959-440X(23)00018-0. [Epub ahead of print]79 102544
    Amino acid sensing and lysosomal signaling complexes.
    Zhicheng Cui, Aaron M N Joiner, Rachel M Jansen, James H Hurley.
      Amino acid pools in the cell are monitored by dedicated sensors, whose structures are now coming into view. The lysosomal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in detail. For FLCN-FNIP, the entire chain of events from the arginine transporter SLC38A9 to substrate-specific mTORC1 activation has been visualized. The structure GATOR2 has been determined, hinting at an ordering of amino acid signaling across a larger size scale than anticipated. The centerpiece of lysosomal signaling, mTORC1, has been revealed to recognize its substrates by more nuanced and substrate-specific mechanisms than previous appreciated. Beyond the well-studied Rag GTPase and mTORC1 machinery, another lysosomal amino acid sensor/effector system, that of PQLC2 and the C9orf72-containing CSW complex, is coming into structural view. These developments hold promise for further insights into lysosomal physiology and lysosome-centric therapeutics.
    DOI:  https://doi.org/10.1016/j.sbi.2023.102544
  2. Cardiovasc Diabetol. 2023 Feb 20. 22(1): 37
    The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy.
    Santosh K Sanganalmath, Shubham Dubey, Sudhakar Veeranki, Keerthy Narisetty, Prasanna Krishnamurthy.
      Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM  has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
    Keywords:  Calcium signaling; Diabetic cardiomyopathy; Exosome; Heart failure; Inflammation; Mitochondrial membrane
    DOI:  https://doi.org/10.1186/s12933-023-01755-1
  3. Nat Commun. 2023 Feb 21. 14(1): 906
    Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts.
    Pei Ying Ng, Amy B P Ribet, Qiang Guo, Benjamin H Mullin, Jamie W Y Tan, Euphemie Landao-Bassonga, Sébastien Stephens, Kai Chen, Jinbo Yuan, Laila Abudulai, Maike Bollen, Edward T T T Nguyen, Jasreen Kular, John M Papadimitriou, Kent Søe, Rohan D Teasdale, Jiake Xu, Robert G Parton, Hiroshi Takayanagi, Nathan J Pavlos.
      Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast's 'resorptive apparatus'. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast's unique secretory organelle and a potential therapeutic target for metabolic bone diseases.
    DOI:  https://doi.org/10.1038/s41467-023-36484-2
  4. Cell Death Dis. 2023 Feb 20. 14(2): 144
    Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming.
    Zhangnan Liu, Mengzhen Fan, Junqing Hou, Sijing Pan, Yanxin Xu, Hailong Zhang, Chen Liu, Xiangjun Hao, Xia Li, Huijuan Wang.
      Serine hydroxymethyltransferase 2 (SHMT2) plays an important role in converting serine to glycine and supplying carbon to one-carbon metabolism to sustain cancer cell proliferation. However, the expression, function, and underlying mechanisms of SHMT2 in clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, we demonstrated that SHMT2 was upregulated in ccRCC tissues compared with controls and associated with patient survival. SHMT2 knockdown inhibited proliferation, migration, and invasion in ccRCC cells. Overexpression of SHMT2 promoted tumor progression. Mechanistically, SHMT2 depletion disrupted one-carbon metabolism, increased reactive oxygen species (ROS) levels, and decreased ATP levels via metabolic reprogramming, which destroyed cell homeostasis. The SHMT2 knockdown-induced stress activated autophagy. A mass of autophagosomes fused with lysosomes, resulting in lysosomal membrane permeabilization (LMP) and leakage of lysosomal contents into the cytoplasm, which eventually led to apoptosis. Our work reveals that SHMT2 functions as an oncogenic gene to promote ccRCC progression. SHMT2 depletion induces apoptosis by causing LMP through excessive activation of the autophagy-lysosome pathway via metabolic reprogramming.
    DOI:  https://doi.org/10.1038/s41419-023-05677-4
  5. Biol Chem. 2023 Feb 23.
    Membrane damage and repair: a thin line between life and death.
    Caroline Barisch, Joost C M Holthuis, Katia Cosentino.
      Bilayered membranes separate cells from their surroundings and form boundaries between intracellular organelles and the cytosol. Gated transport of solutes across membranes enables cells to establish vital ion gradients and a sophisticated metabolic network. However, an advanced compartmentalization of biochemical reactions makes cells also particularly vulnerable to membrane damage inflicted by pathogens, chemicals, inflammatory responses or mechanical stress. To avoid potentially lethal consequences of membrane injuries, cells continuously monitor the structural integrity of their membranes and readily activate appropriate pathways to plug, patch, engulf or shed the damaged membrane area. Here, we review recent insights into the cellular mechanisms that underly an effective maintenance of membrane integrity. We discuss how cells respond to membrane lesions caused by bacterial toxins and endogenous pore-forming proteins, with a primary focus on the intimate crosstalk between membrane proteins and lipids during wound formation, detection and elimination. We also discuss how a delicate balance between membrane damage and repair determines cell fate upon bacterial infection or activation of pro-inflammatory cell death pathways.
    Keywords:   Mycobacterium tuberculosis ; ESCRT; cell death; lysosome; pore-forming proteins; sphingomyelin
    DOI:  https://doi.org/10.1515/hsz-2022-0321
  6. J Cell Sci. 2023 Feb 15. pii: jcs260101. [Epub ahead of print]136(4):
    Ubiquitin and its relatives as wizards of the endolysosomal system.
    Ilana Berlin, Aysegul Sapmaz, Virginie Stévenin, Jacques Neefjes.
      The endolysosomal system comprises a dynamic constellation of vesicles working together to sense and interpret environmental cues and facilitate homeostasis. Integrating extracellular information with the internal affairs of the cell requires endosomes and lysosomes to be proficient in decision-making: fusion or fission; recycling or degradation; fast transport or contacts with other organelles. To effectively discriminate between these options, the endolysosomal system employs complex regulatory strategies that crucially rely on reversible post-translational modifications (PTMs) with ubiquitin (Ub) and ubiquitin-like (Ubl) proteins. The cycle of conjugation, recognition and removal of different Ub- and Ubl-modified states informs cellular protein stability and behavior at spatial and temporal resolution and is thus well suited to finetune macromolecular complex assembly and function on endolysosomal membranes. Here, we discuss how ubiquitylation (also known as ubiquitination) and its biochemical relatives orchestrate endocytic traffic and designate cargo fate, influence membrane identity transitions and support formation of membrane contact sites (MCSs). Finally, we explore the opportunistic hijacking of Ub and Ubl modification cascades by intracellular bacteria that remodel host trafficking pathways to invade and prosper inside cells.
    Keywords:  Bacterial infection; Endosomes; Membrane contact sites; Membrane dynamics; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.260101
  7. Chembiochem. 2023 Feb 23. e202300139
    Lysosomes targeting pH activable imaging-guided photodynamic agents.
    Carlotta Figliola, Halina Anton, Christophe Sutter, Camille Chériaux, Alexandra Sutter, Valérie Mazan, Mourad Elhabiri, Pascal Didier, Denis Jacquemin, Gilles Ulrich.
      Photodynamic therapy (PDT) is a photochemistry-based medical treatment combining light at a specific wavelength and a photosensitizer (PS) in the presence of oxygen. Application of PDT as a conventional treatment is limited and clearly the approval in clinics of new PS is challenging. The selective accumulation of the PS in the targeted malignant cells is of paramount importance to reduce the side effects that are typical of the current worldwide approved PS. Here we report a new series of aniline- and iodine-substituted BODIPY derivatives (1-3) as promising lysosome-targeting and pH-responsive theranostic PS, which displayed a significant in vitro light-induced cytotoxicity, efficient imaging properties and low dark toxicity (for 2 and 3). These compounds were obtained in few reproducible synthetic steps and good yields. Spectroscopic and electrochemical measurements along with computational calculations confirmed the quenching of the emissive properties of the PS, while both fluorescence and 1O2 emission were obtained only under acidic conditions inducing amine protonation. The pKa values and pH-dependent emissive properties of 1-3 being established, their cellular uptake and activation in the lysosomal vesicles (pH ≈ 4-5) were confirmed by their co-localization with the commercial LysoTracker deep red and light-induced cytotoxicity (IC50 between 0.16 and 0.06 µM) against HeLa cancer cells.
    Keywords:  photodynamic therapy, BODIPYs, intraorganellar activation, pH-responsive photosensitizers, selectivity
    DOI:  https://doi.org/10.1002/cbic.202300139
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