bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–03–23
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  2. Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.
  3. Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.
  4. Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
  5. Extracellular chaperones in lysosomal storage diseases.
  6. Lipid juggling: Any1 scrambles membranes for endosome biogenesis.
  7. Ubiquitin-specific protease: an emerging key player in cardiomyopathy.
  1. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  2. Elife. 2025 Mar 17. pii: RP99358. [Epub ahead of print]13
    Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.
    Yuhkoh Satouh, Takaki Tatebe, Isei Tanida, Junji Yamaguchi, Yasuo Uchiyama, Ken Sato.
      Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to metaphase II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed endosomal-lysosomal organellar assemblies (ELYSAs), in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7-8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.
    Keywords:  cell biology; developmental biology; endosome; lysosomal maturation; mouse; oocyte activation; oocyte dormancy; ubiquitination; vacuolar ATPase
    DOI:  https://doi.org/10.7554/eLife.99358
  3. Commun Biol. 2025 Mar 15. 8(1): 443
    Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.
    Iacopo Ruolo, Sara Napolitano, Lorena Postiglione, Gennaro Napolitano, Andrea Ballabio, Diego di Bernardo.
      Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed by activation of the Calcineurin phosphatase, and a slower one driven by inhibition of mTORC1-dependent phosphorylation of TFEB. Upon refeeding, TFEB cytoplasmic relocalisation kinetics are determined by Exportin 1 (XPO1). Collectively, our results show how different mechanisms interact to regulate TFEB activation and the power of microfluidics and quantitative modelling to elucidate complex biological mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-07870-x
  4. J Clin Invest. 2025 Mar 17. pii: e185340. [Epub ahead of print]135(6):
    Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
    Yu-Sheng Yeh, Trent D Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J Schopfer, Adam C Straub, Jaehyung Cho, Irfan J Lodhi, Babak Razani.
      Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
    Keywords:  Adipose tissue; Endocrinology; Lysosomes; Metabolism; Obesity; Therapeutics
    DOI:  https://doi.org/10.1172/JCI185340
  5. Mol Genet Metab. 2025 Mar 15. pii: S1096-7192(25)00077-0. [Epub ahead of print]145(1): 109086
    Extracellular chaperones in lysosomal storage diseases.
    Aslı İnci, Serap Dökmeci.
      Lysosomal storage disorders (LSDs) are a diverse group of inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes due to defective lysosomal function. Recent research has highlighted the pivotal role of extracellular chaperones in the pathophysiology of LSDs, revealing their crucial involvement in modulating disease progression. These chaperones aid in stabilizing and refolding misfolded lysosomal enzymes, enhancing their proper trafficking and function, which in turn reduces substrate accumulation. Furthermore, extracellular chaperones have emerged as promising biomarkers, with their levels in bodily fluids offering potential for disease diagnosis and monitoring. This review explores the current understanding of extracellular chaperones in the context of LSDs, examining their mechanisms of action, biomarker and therapeutic potential, and future directions in clinical application of LSDs.
    Keywords:  Biomarker; Chaperones; Extracellular chaperones; Lysosomal storage disorders; Therapeutic intervention
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109086
  6. J Cell Biol. 2025 Apr 07. pii: e202502158. [Epub ahead of print]224(4):
    Lipid juggling: Any1 scrambles membranes for endosome biogenesis.
    Sinead Iduna Schwabl, Konstantin Adrian Siegmann, David Teis.
      Multivesicular bodies (MVBs) are crucial for membrane protein degradation and lipid homeostasis. A recent study by Gao and colleagues (https://doi.org/10.1083/jcb.202410013) identifies Any1 as a phospholipid scramblase that plays an important role in MVB biogenesis by coordinating membrane remodeling with lipid transfer through Vps13 at organelle contact sites.
    DOI:  https://doi.org/10.1083/jcb.202502158
  7. Cell Commun Signal. 2025 Mar 18. 23(1): 143
    Ubiquitin-specific protease: an emerging key player in cardiomyopathy.
    Danlei Li, Qilin Ma.
      Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.
    Keywords:  Cardiomyopathy; Deubiquitination; PQC; USP
    DOI:  https://doi.org/10.1186/s12964-025-02123-0
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