bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023‒02‒05
seven papers selected by
Satoru Kobayashi
New York Institute of Technology
  1. Mechanisms Controlling Selective Elimination of Damaged Lysosomes.
  2. Lysosomal quality control: molecular mechanisms and therapeutic implications.
  3. Arf5 mediated regulation of mTORC1 at the plasma membrane.
  4. Transcription factor EB regulates phosphatidylinositol-3-phosphate levels that control lysosome positioning in the bladder cancer model.
  5. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.
  6. Effect of ATG12-ATG5-ATG16L1 autophagy E3-like complex on the ability of LC3/GABARAP proteins to induce vesicle tethering and fusion.
  7. Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.
  1. Curr Opin Physiol. 2022 Oct;pii: 100590. [Epub ahead of print]29
    Mechanisms Controlling Selective Elimination of Damaged Lysosomes.
    Melissa J Hoyer, Sharan Swarup, J Wade Harper.
      Lysosomes are subjected to physiological and patho-physiological insults over the course of their life cycle and are accordingly repaired or recycled. Lysophagy, the selective degradation of lysosomes via autophagy, occurs upon unrepairable lysosomal membrane rupture; galectins bind to glycosylated macromolecules in the lysosome lumen, orchestrating a series of cellular responses to promote autophagic recycling of damaged lysosomes and transcriptional upregulation of lysosomal genes. Damaged lysosomes are ubiquitylated, resulting in the recruitment of ubiquitin-binding autophagy receptors, which promote assembly of an autophagosome around damaged lysosomes for delivery to healthy lysosomes for degradation. Here, we review the current state of our understanding of mechanisms used to mark and eliminate damaged lysosomes, and discuss the complexities of galectin function and ubiquitin-chain linkage types. Finally, we discuss the limitations of available data and challenges with the goal of understanding the mechanistic basis of key steps in lysophagic flux.
    DOI:  https://doi.org/10.1016/j.cophys.2022.100590
  2. Trends Cell Biol. 2023 Jan 28. pii: S0962-8924(23)00004-1. [Epub ahead of print]
    Lysosomal quality control: molecular mechanisms and therapeutic implications.
    Haoxiang Yang, Jay Xiaojun Tan.
      Lysosomes are essential catabolic organelles with an acidic lumen and dozens of hydrolytic enzymes. The detrimental consequences of lysosomal leakage have been well known since lysosomes were discovered during the 1950s. However, detailed knowledge of lysosomal quality control mechanisms has only emerged relatively recently. It is now clear that lysosomal leakage triggers multiple lysosomal quality control pathways that replace, remove, or directly repair damaged lysosomes. Here, we review how lysosomal damage is sensed and resolved in mammalian cells, with a focus on the molecular mechanisms underlying different lysosomal quality control pathways. We also discuss the clinical implications and therapeutic potential of these pathways.
    Keywords:  ESCRT; PITT; TFEB/TFE3; lysophagy; lysosomal biogenesis; lysosomal repair
    DOI:  https://doi.org/10.1016/j.tcb.2023.01.001
  3. Mol Biol Cell. 2023 Feb 03. mbcE22070302
    Arf5 mediated regulation of mTORC1 at the plasma membrane.
    Christian Makhoul, Fiona J Houghton, Elizabeth Hinde, Paul A Gleeson.
      The mechanistic target of rapamycin (mTOR) kinase regulates a major signalling pathway in eukaryotic cells. In addition to regulation of mTORC1 at lysosomes, mTORC1 is also localised at other locations. However, little is known about the recruitment and activation of mTORC1 at non-lysosomal sites. To identify regulators of mTORC1 recruitment to non-lysosomal compartments, novel interacting partners with the mTORC1 subunit, Raptor, were identified using immunoprecipitation and mass spectrometry. We show that one of the interacting partners, Arf5, is a novel regulator of mTORC1 signalling at plasma membrane ruffles. Arf5-GFP localizes with endogenous mTOR at PI3,4P2 enriched membrane ruffles together the GTPase required for mTORC1 activation, Rheb. Knockdown of Arf5 reduced the recruitment of mTOR to membrane ruffles. The activation of mTORC1 at membrane ruffles was directly demonstrated using a plasma membrane-targeted mTORC1 biosensor and Arf5 shown to enhance the phosphorylation of the mTORC1 biosensor substrate. In addition, endogenous Arf5 was shown to be required for rapid activation of mTORC1-mediated S6 phosphorylation following nutrient starvation and re-feeding. Our findings reveal a novel Arf5-dependent pathway for recruitment and activation of mTORC1 at plasma membrane ruffles, a process relevant for spatial and temporal regulation of mTORC1 by receptor and nutrient stimuli.
    DOI:  https://doi.org/10.1091/mbc.E22-07-0302
  4. Commun Biol. 2023 Jan 28. 6(1): 114
    Transcription factor EB regulates phosphatidylinositol-3-phosphate levels that control lysosome positioning in the bladder cancer model.
    Pallavi Mathur, Camilla De Barros Santos, Hugo Lachuer, Julie Patat, Bruno Latgé, François Radvanyi, Bruno Goud, Kristine Schauer.
      Lysosomes orchestrate degradation and recycling of exogenous and endogenous material thus controlling cellular homeostasis. Little is known how this organelle changes during cancer. Here we investigate the intracellular landscape of lysosomes in a cellular model of bladder cancer. Employing standardized cell culture on micropatterns we identify a phenotype of peripheral lysosome positioning prevailing in bladder cancer cell lines but not normal urothelium. We show that lysosome positioning is controlled by phosphatidylinositol-3-phosphate (PtdIns3P) levels on endomembranes which recruit FYVE-domain containing proteins for lysosomal dispersion. We identify transcription factor EB (TFEB) as an upstream regulator of PtdIns3P production by VPS34 that is activated in aggressive bladder cancer cells with peripheral lysosomes. This conceptually clarifies the dual role of TFEB as regulator of endosomal maturation and autophagy, two distinct processes controlled by PtdIns3P. Altogether, our findings uncover peripheral lysosome positioning, resulting from PtdIns3P production downstream of TFEB activation, as a potential biomarker for bladder cancer.
    DOI:  https://doi.org/10.1038/s42003-023-04501-1
  5. Nat Metab. 2023 Feb 02.
    AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.
    Xiaoming Dai, Cong Jiang, Qiwei Jiang, Lan Fang, Haihong Yu, Jinhe Guo, Peiqiang Yan, Fangtao Chi, Tao Zhang, Hiroyuki Inuzuka, John M Asara, Ping Wang, Jianping Guo, Wenyi Wei.
      The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth in response to amino acid and glucose levels. However, how mTORC1 senses glucose availability to regulate various downstream signalling pathways remains largely elusive. Here we report that AMP-activated protein kinase (AMPK)-mediated phosphorylation of WDR24, a core component of the GATOR2 complex, has a role in the glucose-sensing capability of mTORC1. Mechanistically, glucose deprivation activates AMPK, which directly phosphorylates WDR24 on S155, subsequently disrupting the integrity of the GATOR2 complex to suppress mTORC1 activation. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity. On the other hand, compared to wild-type littermates, phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity. Our findings reveal that AMPK-mediated phosphorylation of WDR24 modulates glucose-induced mTORC1 activation, thereby providing a rationale for targeting AMPK-WDR24 signalling to fine-tune mTORC1 activation as a potential therapeutic means to combat human diseases with aberrant activation of mTORC1 signalling including cancer.
    DOI:  https://doi.org/10.1038/s42255-022-00732-4
  6. Cell Mol Life Sci. 2023 Feb 02. 80(2): 56
    Effect of ATG12-ATG5-ATG16L1 autophagy E3-like complex on the ability of LC3/GABARAP proteins to induce vesicle tethering and fusion.
    Marina N Iriondo, Asier Etxaniz, Yaiza R Varela, Uxue Ballesteros, Melisa Lázaro, Mikel Valle, Dorotea Fracchiolla, Sascha Martens, L Ruth Montes, Félix M Goñi, Alicia Alonso.
      In macroautophagy, the autophagosome (AP) engulfs portions of cytoplasm to allow their lysosomal degradation. AP formation in humans requires the concerted action of the ATG12 and LC3/GABARAP conjugation systems. The ATG12-ATG5-ATG16L1 or E3-like complex (E3 for short) acts as a ubiquitin-like E3 enzyme, promoting LC3/GABARAP proteins anchoring to the AP membrane. Their role in the AP expansion process is still unclear, in part because there are no studies comparing six LC3/GABARAP family member roles under the same conditions, and also because the full human E3 was only recently available. In the present study, the lipidation of six members of the LC3/GABARAP family has been reconstituted in the presence and absence of E3, and the mechanisms by which E3 and LC3/GABARAP proteins participate in vesicle tethering and fusion have been investigated. In the absence of E3, GABARAP and GABARAPL1 showed the highest activities. Differences found within LC3/GABARAP proteins suggest the existence of a lipidation threshold, lower for the GABARAP subfamily, as a requisite for tethering and inter-vesicular lipid mixing. E3 increases and speeds up lipidation and LC3/GABARAP-promoted tethering. However, E3 hampers LC3/GABARAP capacity to induce inter-vesicular lipid mixing or subsequent fusion, presumably through the formation of a rigid scaffold on the vesicle surface. Our results suggest a model of AP expansion in which the growing regions would be areas where the LC3/GABARAP proteins involved should be susceptible to lipidation in the absence of E3, or else a regulatory mechanism would allow vesicle incorporation and phagophore growth when E3 is present.
    Keywords:  ATG12 UBL system; Autophagosome expansion; Autophagy conjugation systems; Human ATG8; Lipid-protein interaction; Membrane fusion
    DOI:  https://doi.org/10.1007/s00018-023-04704-z
  7. Circ Res. 2023 Feb 03. 132(3): 379-396
    Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.
    Konrad Teodor Sawicki, Adam De Jesus, Hossein Ardehali.
      The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.
    Keywords:  biology; catalysis; electrons; heart; iron; macrophages; metabolism
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321667
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