bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023–12–17
eight papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Lysosomal membrane integrity in fibroblasts derived from patients with Gaucher disease.
  2. Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.
  3. Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.
  4. Lysosomal-mediated drug resistance - fact or illusion?
  5. Cation-independent mannose 6-phosphate receptor: From roles and functions to targeted therapies.
  6. Organelle morphology and positioning orchestrate physiological and disease-associated processes.
  7. Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy.
  8. Gasdermin D-Mediated Pyroptosis in Diabetic Cardiomyopathy: Molecular Mechanisms and Pharmacological Implications.
  1. Cell Struct Funct. 2023 Dec 09.
    Lysosomal membrane integrity in fibroblasts derived from patients with Gaucher disease.
    Asuka Hamamoto, Natsuki Kita, Siddabasave Gowda B Gowda, Hiroyuki Takatsu, Kazuhisa Nakayama, Makoto Arita, Shu-Ping Hui, Hye-Won Shin.
      Gaucher disease (GD) is a recessively inherited lysosomal storage disorder characterized by a deficiency of lysosomal glucocerebrosidase (GBA1). This deficiency results in the accumulation of its substrate, glucosylceramide (GlcCer), within lysosomes. Here, we investigated lysosomal abnormalities in fibroblasts derived from patients with GD. It is noteworthy that the cellular distribution of lysosomes and lysosomal proteolytic activity remained largely unaffected in GD fibroblasts. However, we found that lysosomal membranes of GD fibroblasts were susceptible to damage when exposed to a lysosomotropic agent. Moreover, the susceptibility of lysosomal membranes to a lysosomotropic agent could be partly restored by exogenous expression of wild-type GBA1. Here, we report that the lysosomal membrane integrity is altered in GD fibroblasts, but lysosomal distribution and proteolytic activity is not significantly altered.Key words: glucosylceramide, lysosome, Gaucher disease, lysosomotropic agent.
    Keywords:  Gaucher disease; glucosylceramide; lysosome; lysosomotropic agent
    DOI:  https://doi.org/10.1247/csf.23066
  2. Sci Adv. 2023 Dec 15. 9(50): eadj1205
    Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.
    Prosenjit Pal, Matthew Taylor, Pui Yiu Lam, Francesca Tonelli, Chloe A Hecht, Pawel Lis, Raja S Nirujogi, Toan K Phung, Wondwossen M Yeshaw, Ebsy Jaimon, Rotimi Fasimoye, Emily A Dickie, Melanie Wightman, Thomas Macartney, Suzanne R Pfeffer, Dario R Alessi.
      We demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase-mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
    DOI:  https://doi.org/10.1126/sciadv.adj1205
  3. Cell Rep. 2023 Dec 12. pii: S2211-1247(23)01585-1. [Epub ahead of print]42(12): 113573
    Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.
    Jia-Hui Chen, Na Xu, Lei Qi, Hao-Hao Yan, Fang-Yan Wan, Feng Gao, Chuanhai Fu, Chunlei Cang, Boxun Lu, Guo-Qiang Bi, Ai-Hui Tang.
      Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.
    Keywords:  CAG-140 mice; CP: Cell biology; CP: Neuroscience; hippocampus; light-induced dimerization; long-term potentiation; lysosome; optogenetic
    DOI:  https://doi.org/10.1016/j.celrep.2023.113573
  4. Pharmacol Res. 2023 Dec 09. pii: S1043-6618(23)00381-X. [Epub ahead of print] 107025
    Lysosomal-mediated drug resistance - fact or illusion?
    Petr Mlejnek.
      
    DOI:  https://doi.org/10.1016/j.phrs.2023.107025
  5. J Control Release. 2023 Dec 10. pii: S0168-3659(23)00798-8. [Epub ahead of print]
    Cation-independent mannose 6-phosphate receptor: From roles and functions to targeted therapies.
    Corentin Gauthier, Khaled El Cheikh, Ilaria Basile, Morgane Daurat, Elodie Morère, Marcel Garcia, Marie Maynadier, Alain Morère, Magali Gary-Bobo.
      The cation-independent mannose 6-phosphate receptor (CI-M6PR) is a ubiquitous transmembrane receptor whose main intracellular role is to direct enzymes carrying mannose 6-phosphate moieties to lysosomal compartments. Recently, the small membrane-bound portion of this receptor has appeared to be implicated in numerous pathophysiological processes. This review presents an overview of the main ligand partners and the roles of CI-M6PR in lysosomal storage diseases, neurology, immunology and cancer fields. Moreover, this membrane receptor has already been noted for its strong potential in therapeutic applications thanks to its cellular internalization activity and its ability to address pathogenic factors to lysosomes for degradation. A number of therapeutic delivery approaches using CI-M6PR, in particular with enzymes, antibodies or nanoparticles, are currently being proposed.
    Keywords:  Brain diseases; CI-M6PR targeting; Cancers; Immune system; Lysosomal storage disorders
    DOI:  https://doi.org/10.1016/j.jconrel.2023.12.014
  6. Curr Opin Cell Biol. 2023 Dec 13. pii: S0955-0674(23)00142-4. [Epub ahead of print]86 102293
    Organelle morphology and positioning orchestrate physiological and disease-associated processes.
    Katerina Jerabkova-Roda, Rituraj Marwaha, Tamal Das, Jacky G Goetz.
      In cells, organelles are distributed nonrandomly to regulate cells' physiological and disease-associated processes. Based on their morphology, position within the cell, and contacts with other organelles, they exert different biological functions. Endo-lysosomes are critical cell metabolism and nutrient-sensing regulators modulating cell growth and cellular adaptation in response to nutrient availability. Their spatial distribution is intimately linked to their function. In this review, we will discuss the role of endolysosomes under physiological conditions and in the context of cancer progression, with a special focus on their morphology, the molecular mechanisms determining their subcellular position, and the contacts they form with other organelles. We aim to highlight the relationship between cell architecture and cell function and its impact on maintaining organismal homeostasis.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102293
  7. Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01541-3. [Epub ahead of print]42(12): 113529
    Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy.
    Gregory J Krause, Philipp Kirchner, Barbara Stiller, Kateryna Morozova, Antonio Diaz, Kuei-Ho Chen, Nevan J Krogan, Esperanza Agullo-Pascual, Cristina C Clement, Kristen Lindenau, Danielle L Swaney, Shilpa Dilipkumar, Jose Javier Bravo-Cordero, Laura Santambrogio, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
    Keywords:  Bag6; CP: Molecular biology; autophagy; chaperone; late endosome; lysosome; microautophagy; protein degradation; protein targeting; proteostasis; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113529
  8. Molecules. 2023 Nov 28. pii: 7813. [Epub ahead of print]28(23):
    Gasdermin D-Mediated Pyroptosis in Diabetic Cardiomyopathy: Molecular Mechanisms and Pharmacological Implications.
    Zhou Liu, Yifan Chen, Yu Mei, Meiling Yan, Haihai Liang.
      Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus (DM), which can lead to heart failure (HF). One of the most important cellular processes associated with DCM is the death of cardiomyocytes. Gasdermin D (GSDMD) plays a key role in mediating pyroptosis, a type of programmed cell death closely associated with inflammasome activation. Recent studies have revealed that pyroptosis is induced during hyperglycemia, which is crucial to the development of DCM. Although the effects of pyroptosis on DCM have been discussed, the relationship between DCM and GSDMD is not fully clarified. Recent studies gave us the impetus for clarifying the meaning of GSDMD in DCM. The purpose of this review is to summarize new and emerging insights, mainly discussing the structures of GSDMD and the mechanism of pore formation, activation pathways, molecular mechanisms of GSDMD-mediated pyroptosis, and the therapeutic potential of GSDMD in DCM. The implications of this review will pave the way for a new therapeutic target in DCM.
    Keywords:  Gasdermin D; diabetic cardiomyopathy; heart; inflammasomes; pyroptosis
    DOI:  https://doi.org/10.3390/molecules28237813
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