bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023‒11‒05
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis.
  2. Revealing Mitochondrion-Lysosome Dynamic Interactions and pH Variations in Live Cells with a pH-Sensitive Fluorescent Probe.
  3. Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.
  4. Cholesterol regulates insulin-induced mTORC1 signaling.
  5. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function.
  6. The mechanism of Atg15-mediated membrane disruption in autophagy.
  7. The evolution and diversity of actin-dependent cell migration.
  1. Autophagy. 2023 Nov 01. 1-17
    SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis.
    Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu, Jiachen Xu, Shanhu Li, Lingqiang Zhang, Lei Dong.
      Macroautophagy/autophagy is a homeostatic process in response to multiple signaling, such as the lysosome-dependent recycling process of cellular components. Starvation-induced MTOR inactivation and PPP3/calcineurin activation were shown to promote the nuclear translocation of TFEB. However, the mechanisms via which signals from endomembrane damage are transmitted to activate PPP3/calcineurin and orchestrate autophagic responses remain unknown. This study aimed to show that autophagy regulator SMURF1 controlled TFEB nuclear import for transcriptional activation of the lysosomal biogenesis. We showed that blocking SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation. It revealed galectins recognized endolysosomal damage, and led to recruitment of SMURF1 and the PPP3/calcineurin apparatus on lysosomes. SMURF1 interacts with both LGALS3 and PPP3CB to form the LGALS3-SMURF1-PPP3/calcineurin complex. Importantly, this complex further stabilizes TFEB, thereby activating TFEB for lysosomal biogenesis. We determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition. In addition, SMURF1 is required for PPP3/calcineurin activity as a positive regulator of TFEB. SMURF1 controlled the phosphatase activity of the PPP3CB by promoting the dissociation of its autoinhibitory domain (AID) from its catalytic domain (CD). Overexpression of SMURF1 showed similar effects as the constitutive activation of PPP3CB. Thus, SMURF1, which bridges environmental stress with the core autophagosomal and autolysosomal machinery, interacted with endomembrane sensor LGALS3 and phosphatase PPP3CB to control TFEB activation.Abbreviations: ATG: autophagy-related; LLOMe: L-Leucyl-L-Leucine methyl ester; ML-SA1: mucolipin synthetic agonist 1; MTOR: mechanistic target of rapamycin kinase; PPP3CB: protein phosphatase 3 catalytic subunit beta; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; TFEB: transcription factor EB.
    Keywords:  Autophagy; PPP3/Calcineurin; SMURF1; TFEB; lysosomal biogenesis
    DOI:  https://doi.org/10.1080/15548627.2023.2267413
  2. Anal Chem. 2023 Nov 02.
    Revealing Mitochondrion-Lysosome Dynamic Interactions and pH Variations in Live Cells with a pH-Sensitive Fluorescent Probe.
    Jian Wang, Jia-Tong Yan, Shu-Tang Zeng, Wen Shao, Gui-Xue Tang, Shuo-Bin Chen, Zhi-Shu Huang, Jia-Heng Tan, Xiu-Cai Chen.
      Mitochondrion-lysosome interactions have garnered significant attention in recent research. Numerous studies have shown that mitochondrion-lysosome interactions, including mitochondrion-lysosome contact (MLC) and mitophagy, are involved in various biological processes and pathological conditions. Single fluorescent probes are termed a pivotal chemical tool in unraveling the intricate spatiotemporal interorganelle interplay in live cells. However, current chemical tools are insufficient to deeply understand mitochondrion-lysosome dynamic interactions and related diseases, Moreover, the rational design of mitochondrion-lysosome dual-targeting fluorescent probes is intractable. Herein, we designed and synthesized a pH-sensitive fluorescent probe called INSA, which could simultaneously light up mitochondria (red emission) and lysosomes (green emission) for their internal pH differences. Employing INSA, we successfully recorded long-term dynamic interactions between lysosomes and mitochondria. More importantly, the increasing mitochondrion-lysosome interactions in ferroptotic cells were also revealed by INSA. Further, we observed pH variations in mitochondria and lysosomes during ferroptosis for the first time. In brief, this work not only introduced a pH-sensitive fluorescent probe INSA for the disclosure of the mitochondrion-lysosome dynamic interplays but also pioneered the visualization of the organellar pH alternation in a specific disease model.
    DOI:  https://doi.org/10.1021/acs.analchem.3c02878
  3. J Cell Biol. 2023 Dec 04. pii: e202305032. [Epub ahead of print]222(12):
    Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.
    Eric D Leisten, Abby C Woods, Yvette C Wong.
      Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria and lysosomes, including co-regulation of Rab7 GTP hydrolysis and Drp1 GTP hydrolysis. Here, we highlight recent findings and future perspectives on this dynamic pathway and its roles in health and disease.
    DOI:  https://doi.org/10.1083/jcb.202305032
  4. J Cell Sci. 2023 Nov 03. pii: jcs.261402. [Epub ahead of print]
    Cholesterol regulates insulin-induced mTORC1 signaling.
    Kolaparamba V Navyasree, Shikha T Ramesh, Perunthottathu K Umasankar.
      The rapid activation of the critical kinase, mechanistic target of rapamycin complex-1 (mTORC1) by insulin is key to cell growth in mammals, but the regulatory factors remain unclear. Here, we demonstrate that cholesterol plays a crucial role in the regulation of insulin-stimulated mTORC1 signaling. The rapid progression of insulin-induced mTORC1 signaling declines in sterol-depleted cells and restores in cholesterol-repleted cells. In insulin-stimulated cells, cholesterol promotes recruitment of mTORC1 onto lysosomes without affecting insulin-induced dissociation of the TSC complex from lysosomes, thereby enabling complete activation of mTORC1. We also show that under prolonged starvation conditions, cholesterol coordinates with autophagy to support mTORC1 reactivation on lysosomes thereby restoring insulin-responsive mTORC1 signaling. Further, we identify that Smith-Lemli-Opitz Syndrome (SLOS) patient fibroblasts and HeLa-SLOS model which are deficient in cholesterol biosynthesis exhibit defects in insulin-mTORC1 growth axis. These defects are rescued by supplementation of exogenous cholesterol or by expression of constitutively active Rag GTPase, a downstream activator of mTORC1. Overall, our findings propose novel signal integration mechanisms to achieve spatial and temporal control of mTORC1-dependent growth signaling and their aberrations in disease.
    Keywords:  Cholesterol; Insulin; Lysosome; Signaling; mTORC1
    DOI:  https://doi.org/10.1242/jcs.261402
  5. Theranostics. 2023 ;13(15): 5435-5451
    Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function.
    Yohan Santin, Karina Formoso, Fraha Haidar, Maria Del Pilar Oreja Fuentes, Florence Bourgailh, Nesrine Hifdi, Karim Hnia, Yosra Doghri, Jessica Resta, Camille Champigny, Séverine Lechevallier, Maximin Détrait, Grégoire Cousin, Malik Bisserier, Angelo Parini, Frank Lezoualc'h, Marc Verelst, Jeanne Mialet-Perez.
      Doxorubicin (Dox) is an effective anticancer molecule, but its clinical efficacy is limited by strong cardiotoxic side effects. Lysosomal dysfunction has recently been proposed as a new mechanism of Dox-induced cardiomyopathy. However, to date, there is a paucity of therapeutic approaches capable of restoring lysosomal acidification and function in the heart. Methods: We designed novel poly(lactic-co-glycolic acid) (PLGA)-grafted silica nanoparticles (NPs) and investigated their therapeutic potential in the primary prevention of Dox cardiotoxicity in cardiomyocytes and mice. Results: We showed that NPs-PLGA internalized rapidly in cardiomyocytes and accumulated inside the lysosomes. Mechanistically, NPs-PLGA restored lysosomal acidification in the presence of doxorubicin or bafilomycin A1, thereby improving lysosomal function and autophagic flux. Importantly, NPs-PLGA mitigated Dox-related mitochondrial dysfunction and oxidative stress, two main mechanisms of cardiotoxicity. In vivo, inhalation of NPs-PLGA led to effective and rapid targeting of the myocardium, which prevented Dox-induced adverse remodeling and cardiac dysfunction in mice. Conclusion: Our findings demonstrate a pivotal role for lysosomal dysfunction in Dox-induced cardiomyopathy and highlight for the first time that pulmonary-driven NPs-PLGA administration is a promising strategy against anthracycline cardiotoxicity.
    Keywords:  autophagy; cardiotoxicity; doxorubicin; lysosomes; nanoparticles
    DOI:  https://doi.org/10.7150/thno.86310
  6. J Cell Biol. 2023 Dec 04. pii: e202306120. [Epub ahead of print]222(12):
    The mechanism of Atg15-mediated membrane disruption in autophagy.
    Yoko Kagohashi, Michiko Sasaki, Alexander I May, Tomoko Kawamata, Yoshinori Ohsumi.
      Autophagy is a lysosomal/vacuolar delivery system that degrades cytoplasmic material. During autophagy, autophagosomes deliver cellular components to the vacuole, resulting in the release of a cargo-containing autophagic body (AB) into the vacuole. AB membranes must be disrupted for degradation of cargo to occur. The lipase Atg15 and vacuolar proteases Pep4 and Prb1 are known to be necessary for this disruption and cargo degradation, but the mechanistic underpinnings remain unclear. In this study, we establish a system to detect lipase activity in the vacuole and show that Atg15 is the sole vacuolar phospholipase. Pep4 and Prb1 are required for the activation of Atg15 lipase function, which occurs following delivery of Atg15 to the vacuole by the MVB pathway. In vitro experiments reveal that Atg15 is a phospholipase B of broad substrate specificity that is likely implicated in the disruption of a range of membranes. Further, we use isolated ABs to demonstrate that Atg15 alone is able to disrupt AB membranes.
    DOI:  https://doi.org/10.1083/jcb.202306120
  7. Mol Biol Cell. 2023 Nov 01. 34(12): pe6
    The evolution and diversity of actin-dependent cell migration.
    Lillian K Fritz-Laylin, Margaret A Titus.
      Many eukaryotic cells, including animal cells and unicellular amoebae, use dynamic-actin networks to crawl across solid surfaces. Recent discoveries of actin-dependent crawling in additional lineages have sparked interest in understanding how and when this type of motility evolved. Tracing the evolution of cell crawling requires understanding the molecular mechanisms underlying motility. Here we outline what is known about the diversity and evolution of the molecular mechanisms that drive cell motility, with a focus on actin-dependent crawling. Classic studies and recent work have revealed a surprising number of distinct mechanical modes of actin-dependent crawling used by different cell types and species to navigate different environments. The overlap in actin network regulators driving multiple types of actin-dependent crawling, along with cortical-actin networks that support the plasma membrane in these cells, suggest that actin motility and cortical actin networks might have a common evolutionary origin. The rapid development of additional evolutionarily diverse model systems, advanced imaging technologies, and CRISPR-based genetic tools, is opening the door to testing these and other new ideas about the evolution of actin-dependent cell crawling.
    DOI:  https://doi.org/10.1091/mbc.E22-08-0358
This page is being maintained by Thomas Krichel. It was last updated on 2023‒11‒05 at 14:23.