bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024‒09‒29
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.
  2. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  3. USF2 and TFEB compete in regulating lysosomal and autophagy genes.
  4. Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
  5. Membrane remodeling via ubiquitin-mediated pathways.
  6. Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.
  7. Role of ferroptosis in the pathogenesis of heart disease.
  1. Autophagy. 2024 Sep 26.
    SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.
    Qin Xia, Xuan Liu, Lu Zhong, Jun Qu, Lei Dong.
      The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.
    Keywords:  Autophagy; PPP3/calcineurin; SMURF1; TFEB; lysosomal homeostasis
    DOI:  https://doi.org/10.1080/15548627.2024.2407709
  2. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  3. Nat Commun. 2024 Sep 27. 15(1): 8334
    USF2 and TFEB compete in regulating lysosomal and autophagy genes.
    Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim, Sung Hee Baek.
      Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52600-2
  4. FEBS J. 2024 Sep 26.
    Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
    Phineas Smith, Bernadette Carroll.
      Ageing is defined as the progressive loss of tissue function and regenerative capacity and is caused by both intrinsic factors i.e. the natural accumulation of damage, and extrinsic factors i.e. damage from environmental stressors. Cellular senescence, in brief, is an irreversible exit from the cell cycle that occurs primarily in response to excessive cellular damage, such as from ultraviolet (UV) exposure and oxidative stress, and it has been comprehensively demonstrated to contribute to tissue and organismal ageing. In this review, we will focus on the skin, an organ which acts as an essential protective barrier against injury, insults, and infection. We will explore the evidence for the existence and contribution of cellular senescence to skin ageing. We discuss the known molecular mechanisms driving senescence in the skin, with a focus on the dysregulation of the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1). We explore the interplay of dysregulated mTORC1 with lysosomes and how they contribute to senescence phenotypes.
    Keywords:  ageing; lysosome; mTORC1; senescence; skin
    DOI:  https://doi.org/10.1111/febs.17281
  5. Cell Chem Biol. 2024 Sep 19. pii: S2451-9456(24)00356-8. [Epub ahead of print]31(9): 1627-1635
    Membrane remodeling via ubiquitin-mediated pathways.
    Anne-Claire Jacomin, Ivan Dikic.
      The dynamic process of membrane shaping and remodeling plays a vital role in cellular functions, with proteins and cellular membranes interacting intricately to adapt to various cellular needs and environmental cues. Ubiquitination-a posttranslational modification-was shown to be essential in regulating membrane structure and shape. It influences virtually all pathways relying on cellular membranes, such as endocytosis and autophagy by directing protein degradation, sorting, and oligomerization. Ubiquitin is mostly known as a protein modifier; however, it was reported that ubiquitin and ubiquitin-like proteins can associate directly with lipids, affecting membrane curvature and dynamics. In this review, we summarize some of the current knowledge on ubiquitin-mediated membrane remodeling in the context of endocytosis, autophagy, and ER-phagy.
    Keywords:  ER remodeling; ER-phagy; ESCRT; autophagy; membrane remodeling; ubiquitin
    DOI:  https://doi.org/10.1016/j.chembiol.2024.08.007
  6. Traffic. 2024 Sep;25(9): e12956
    Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.
    Aliye Ezgi Güleç Taşkıran, Hepşen H Hüsnügil, Zahra E Soltani, Göksu Oral, Nazlı S Menemenli, Chuanpit Hampel, Kerstin Huebner, Katharina Erlenbach-Wuensch, Ilir Sheraj, Regine Schneider-Stock, Aytekin Akyol, Nalan Liv, Sreeparna Banerjee.
      Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.
    Keywords:  Rab7a; chemoresponse; drug trapping; lysosome; nutrient limitation
    DOI:  https://doi.org/10.1111/tra.12956
  7. Front Physiol. 2024 ;15 1450656
    Role of ferroptosis in the pathogenesis of heart disease.
    Sulail Fatima, Haiyan Zhou, Yi Chen, Qinghang Liu.
      Ferroptosis is a new form of regulated necrosis characterized by iron-dependent lipid peroxidation, leading to irreparable lipid damage, membrane permeabilization, and necrotic cell death. Ferroptosis has recently been implicated in the pathogenesis of multiple forms of heart disease such as myocardial infarction, cardiac hypertrophy, heart failure, and various cardiomyopathies. Important progress has also been made regarding how ferroptosis is regulated in vitro and in vivo as well as its role in cardiac homeostasis and disease pathogenesis. In this review, we discuss molecular mechanisms that regulates ferroptosis in the heart, including pathways leading to iron overload and lipid peroxidation as well as the roles of key organelles in this process. We also discuss recent findings pertaining to the new pathogenic role of ferroptosis in various forms of heart disease as well as genetic and pharmacologic strategies targeting ferroptosis in the heart.
    Keywords:  ferroptosis; heart disease; iron overload; lipid peroxidation; signaling
    DOI:  https://doi.org/10.3389/fphys.2024.1450656
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