bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024–11–10
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. mTORC1 activity licenses its own release from the lysosomal surface.
  2. mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.
  3. The USP12/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation.
  4. Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
  5. Lysosomal enzyme binding to the cation-independent mannose 6-phosphate receptor is regulated allosterically by insulin-like growth factor 2.
  6. Diabetic Cardiomyopathy: What Clinicians Should Know.
  7. Role of glycogen in cardiac metabolic stress.
  1. Mol Cell. 2024 Oct 25. pii: S1097-2765(24)00831-1. [Epub ahead of print]
    mTORC1 activity licenses its own release from the lysosomal surface.
    Aishwarya Acharya, Constantinos Demetriades.
      Nutrient signaling converges on mTORC1, which, in turn, orchestrates a physiological cellular response. A key determinant of mTORC1 activity is its shuttling between the lysosomal surface and the cytoplasm, with nutrients promoting its recruitment to lysosomes by the Rag GTPases. Active mTORC1 regulates various cellular functions by phosphorylating distinct substrates at different subcellular locations. Importantly, how mTORC1 that is activated on lysosomes is released to meet its non-lysosomal targets and whether mTORC1 activity itself impacts its localization remain unclear. Here, we show that, in human cells, mTORC1 inhibition prevents its release from lysosomes, even under starvation conditions, which is accompanied by elevated and sustained phosphorylation of its lysosomal substrate TFEB. Mechanistically, "inactive" mTORC1 causes persistent Rag activation, underlining its release as another process actively mediated via the Rags. In sum, we describe a mechanism by which mTORC1 controls its own localization, likely to prevent futile cycling on and off lysosomes.
    Keywords:  GATOR1; Rag GTPases; Rheb; TFE3; TFEB; Torin1; lysosomes; mTORC1; rapamycin
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.008
  2. Mol Cell. 2024 Oct 25. pii: S1097-2765(24)00832-3. [Epub ahead of print]
    mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.
    Susan Zwakenberg, Denise Westland, Robert M van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M Verhoeven-Duif, Judith J M Jans, Harmjan R Vos, Eleonora Aronica, Fried J T Zwartkruis.
      To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).
    Keywords:  FCD IIb; NPRL2; Rag GTPases; Rheb; TFE3; TSC; amino acids; lysosomes; mTORC1
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.009
  3. EMBO Rep. 2024 Nov 06.
    The USP12/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation.
    Kaikai Yu, Guan M Wang, Shiny Shengzhen Guo, Florian Bassermann, Reinhard Fässler.
      The functions of integrins are tightly regulated via multiple mechanisms including trafficking and degradation. Integrins are repeatedly internalized, routed into the endosomal system and either degraded by the lysosome or recycled back to the plasma membrane. The ubiquitin system dictates whether internalized proteins are degraded or recycled. Here, we use a genetic screen and proximity-dependent biotin identification to identify deubiquitinase(s) that control integrin surface levels. We find that a ternary deubiquitinating complex, comprised of USP12 (or the homologous USP46), WDR48 and WDR20, stabilizes β1 integrin (Itgb1) by preventing ESCRT-mediated lysosomal degradation. Mechanistically, the USP12/46-WDR48-WDR20 complex removes ubiquitin from the cytoplasmic tail of internalized Itgb1 in early endosomes, which in turn prevents ESCRT-mediated sorting and Itgb1 degradation.
    Keywords:  DUB; ESCRT; Integrin; USP12/USP46; Ubiquitination
    DOI:  https://doi.org/10.1038/s44319-024-00300-9
  4. J Cell Biol. 2025 Jan 06. pii: e202403104. [Epub ahead of print]224(1):
    Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
    Xinghua Feng, Weijie Cai, Qian Li, Liding Zhao, Yaping Meng, Haoxing Xu.
      Elevated levels of plasma-free fatty acids and oxidative stress have been identified as putative primary pathogenic factors in endothelial dysfunction etiology, though their roles are unclear. In human endothelial cells, we found that saturated fatty acids (SFAs)-including the plasma-predominant palmitic acid (PA)-cause mitochondrial fragmentation and elevation of intracellular reactive oxygen species (ROS) levels. TRPML1 is a lysosomal ROS-sensitive Ca2+ channel that regulates lysosomal trafficking and biogenesis. Small-molecule agonists of TRPML1 prevented PA-induced mitochondrial damage and ROS elevation through activation of transcriptional factor EB (TFEB), which boosts lysosome biogenesis and mitophagy. Whereas genetically silencing TRPML1 abolished the protective effects of TRPML1 agonism, TRPML1 overexpression conferred a full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in SFA-damaged endothelial cells. The present results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases.
    DOI:  https://doi.org/10.1083/jcb.202403104
  5. Sci Rep. 2024 11 06. 14(1): 26875
    Lysosomal enzyme binding to the cation-independent mannose 6-phosphate receptor is regulated allosterically by insulin-like growth factor 2.
    Richard N Bohnsack, Sandeep K Misra, Jianfang Liu, Mayumi Ishihara-Aoki, Michaela Pereckas, Kazuhiro Aoki, Gang Ren, Joshua S Sharp, Nancy M Dahms.
      The cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor's conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.
    DOI:  https://doi.org/10.1038/s41598-024-75300-9
  6. Am J Med. 2024 Nov 04. pii: S0002-9343(24)00695-8. [Epub ahead of print]
    Diabetic Cardiomyopathy: What Clinicians Should Know.
    Hannah Smati, Yusuf Kamran Qadeer, Mario Rodriguez, Errol Moras, Gregg C Fonarow, Scott D Isaacs, Thomas H Marwick, Chayakrit Krittanawong.
      Diabetes has classically been associated with atherosclerotic cardiovascular disease. However, heart failure is now increasingly recognized as a prevalent and often first cardiovascular complication among patients with diabetes. Investigation of this epidemiological relationship has led to recognition of diabetic cardiomyopathy, or structural heart disease that develops in patients with diabetes and may lead to progressive heart failure independently of coronary artery disease or conventional cardiovascular risk factors such as hypertension. Despite increased awareness, clinical management of this common cardiovascular complication remains challenging, with no consensus on its diagnosis or treatment. The lack of specific therapy has been recognized as an unmet clinical need. In this review, we summarize current understanding of the hallmark metabolic and structural changes of diabetic cardiomyopathy, appraise current tools for diagnosis and staging among patients, and describe the emerging but still preclinical data on therapeutic options.
    Keywords:  Diabetic cardiomyopathy; diabetes mellitus; heart failure; myocardial fibrosis
    DOI:  https://doi.org/10.1016/j.amjmed.2024.10.026
  7. Metabolism. 2024 Nov 03. pii: S0026-0495(24)00287-7. [Epub ahead of print] 156059
    Role of glycogen in cardiac metabolic stress.
    Ke-Fa Xiang, Jing-Jing Wan, Peng-Yuan Wang, Xia Liu.
      Metabolic stress in the myocardium arises from a diverse array of acute and chronic pathophysiological contexts. Glycogen mishandling is a key feature of metabolic stress, while maladaptation in energy-stress situations confers functional deficits. Cardiac glycogen serves as a pivotal reserve for myocardial energy, which is classically described as an energy source and contributes to glucose homeostasis during hypoxia or ischemia. Despite extensive research activity, how glycogen metabolism affects cardiovascular disease remains unclear. In this review, we focus on its regulation across myocardial energy metabolism in response to stress, and its role in metabolism, immunity, and autophagy. We further summarize the cardiovascular-related drugs regulating glycogen metabolism. In this way, we provide current knowledge for the understanding of glycogen metabolism in the myocardium.
    Keywords:  Autophagy; Cardiac glycogen; Glycolysis; Immune regulation; Lipid metabolism; Metabolic stress; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.metabol.2024.156059
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