bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–03–02
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons.
  2. Reversing lysosomal dysfunction to treat PAH.
  3. The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.
  4. Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
  5. A "turn-on" intracellular pH probe for the quantitative monitoring of lysosomal alkalization in living cells.
  6. Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling.
  7. Autophagy in High-Fat Diet and Streptozotocin-Induced Metabolic Cardiomyopathy: Mechanisms and Therapeutic Implications.
  8. Lysosomal degradation of ER client proteins by ER-phagy and related pathways.
  9. Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.
  1. Nat Commun. 2024 Dec 30. 15(1): 10829
    Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons.
    Chun Hei Li, Noortje Kersten, Nazmiye Özkan, Dan T M Nguyen, Max Koppers, Harm Post, Maarten Altelaar, Ginny G Farias.
      Lysosomes are membrane-bound organelles critical for maintaining cellular homeostasis. Delivery of biosynthetic lysosomal proteins to lysosomes is crucial to orchestrate proper lysosomal function. However, it remains unknown how the delivery of biosynthetic lysosomal proteins to lysosomes is ensured in neurons, which are highly polarized cells. Here, we developed Protein Origin, Trafficking And Targeting to Organelle Mapping (POTATOMap), by combining trafficking synchronization and proximity-labelling based proteomics, to unravel the trafficking routes and interactome of the biosynthetic lysosomal membrane protein LAMP1 at specified time points. This approach, combined with advanced microscopy, enables us to identify the neuronal domain-specific trafficking machineries of biosynthetic LAMP1. We reveal a role in replenishing axonal lysosomes, in delivery of newly synthesized axonal synaptic proteins, and interactions with RNA granules to facilitate hitchhiking in the axon. POTATOMap offers a robust approach to map out dynamic biosynthetic protein trafficking and interactome from their origin to destination.
    DOI:  https://doi.org/10.1038/s41467-024-55052-w
  2. Nat Rev Drug Discov. 2025 Feb 24.
    Reversing lysosomal dysfunction to treat PAH.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-025-00035-9
  3. EMBO Rep. 2025 Feb 27.
    The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.
    Ori Scott, Ekambir Saran, Spencer A Freeman.
      Cells and tissues turn over their aged and damaged components in order to adapt to a changing environment and maintain homeostasis. These functions rely on lysosomes, dynamic and heterogeneous organelles that play essential roles in nutrient redistribution, metabolism, signaling, gene regulation, plasma membrane repair, and immunity. Because of metabolic fluctuations and pathogenic threats, lysosomes must adapt in the short and long term to maintain functionality. In response to such challenges, lysosomes deploy a variety of mechanisms that prevent the breaching of their membrane and escape of their contents, including pathogen-associated molecules and hydrolases. While transient permeabilization of the lysosomal membrane can have acute beneficial effects, supporting inflammation and antigen cross-presentation, sustained or repeated lysosomal perforations have adverse metabolic and transcriptional consequences and can lead to cell death. This review outlines factors contributing to lysosomal stress and damage perception, as well as remedial processes aimed at addressing lysosomal disruptions. We conclude that lysosomal stress plays widespread roles in human physiology and pathology, the understanding and manipulation of which can open the door to novel therapeutic strategies.
    Keywords:  Autophagy; Glycocalyx; Host–pathogen; Phagosolysosome; Pore-forming Toxins
    DOI:  https://doi.org/10.1038/s44319-025-00405-9
  4. Antioxidants (Basel). 2025 Jan 22. pii: 125. [Epub ahead of print]14(2):
    Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
    Szilvia Kiraly, Jack Stanley, Emily R Eden.
      The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria-lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome-mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.
    Keywords:  crosstalk; lysosomes; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.3390/antiox14020125
  5. Biosens Bioelectron. 2025 Feb 19. pii: S0956-5663(25)00159-9. [Epub ahead of print]277 117285
    A "turn-on" intracellular pH probe for the quantitative monitoring of lysosomal alkalization in living cells.
    Hejian Ke, Jiaqi Yang, Wanping Zhang, Pengli Yang, Yiwu Wang, Ningrong Wang, Jiahao Bai, Huaiyi Yin, Yanyan Chen, Xinhong Chen, Peishan Fu, Yongjun Gan, Guangchao Zang, Qian Liu.
      A slight elevation in lysosomal pH can lead to indigestion or nonspecific hydrolysis, thereby increasing the risk of various neurodegenerative diseases and cancer. Therefore, accurate monitoring of lysosomal pH changes in living cells is essential for the diagnosis and treatment of such diseases, despite the significant challenges involved. In this study, we synthesized a pH-dependent fluorescent probe, B26, which comprises 1,8-naphthalimide as the fluorescent chromophore, an N-(2-hydroxyethyl) piperazine group for lysosome targeting, and a hydroxyethyl group to increase solubility and regulate pKa. B26 demonstrated high sensitivity, selectivity, and reversibility in response to H+, and exhibited a remarkable 98-fold increase in fluorescence intensity between pH 2.0 and pH 11.0, with a pKa value of 7.0, highlighting its "turn-on" fluorescence property. Density functional theory calculations and 1H NMR titration revealed that the pH-sensing mechanism of B26 relies on the inhibition of photoinduced electron transfer from the N-(2-hydroxyethyl) piperazine group to the naphthalimide moiety under acidic conditions. Importantly, B26 effectively labeled lysosomes and displayed significant sensitivity to pH changes, facilitating the quantitative detection of pH shifts during lysosomal alkalization in living cells due to its elevated pKa. These findings suggest that B26 successfully addresses the limitations of existing lysosomal pH probes, particularly in detecting pH changes within the near-neutral range. Furthermore, both the zebrafish model and subcutaneous imaging support the application of B26 in in vivo settings. Given its exceptional properties, B26 holds enormous potential for the research and diagnosis of pH-related diseases.
    Keywords:  Fluorescence probe; Living cell imaging; Lysosomal alkalization; Lysosomal pH monitoring; pH sensing
    DOI:  https://doi.org/10.1016/j.bios.2025.117285
  6. Science. 2025 Feb 28. 387(6737): eadp4120
    Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling.
    Kaixin Ding, Zhipeng Zhang, Zhengbin Han, Lei Shi, Xinzhi Li, Yutong Liu, Zhenzhi Li, Chongchong Zhao, Yifeng Cui, Liying Zhou, Bolin Xu, Wenjing Zhou, Yikui Zhao, Zhiqiang Wang, He Huang, Liwei Xie, Xiao-Wei Chen, Zheng Chen.
      Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N6-methyladenosine (m6A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.
    DOI:  https://doi.org/10.1126/science.adp4120
  7. Int J Mol Sci. 2025 Feb 15. pii: 1668. [Epub ahead of print]26(4):
    Autophagy in High-Fat Diet and Streptozotocin-Induced Metabolic Cardiomyopathy: Mechanisms and Therapeutic Implications.
    Rong Zhou, Zutong Zhang, Xinjie Li, Qinchun Duan, Yuanlin Miao, Tingting Zhang, Mofei Wang, Jiali Li, Wei Zhang, Liyang Wang, Odell D Jones, Mengmeng Xu, Yingli Liu, Xuehong Xu.
      Metabolic cardiomyopathy, encompassing diabetic and obese cardiomyopathy, is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 and type 2 diabetes, and obesity. These conditions induce structural and functional alterations in the heart, including left ventricular dysfunction, fibrosis, and ultimately heart failure, particularly in the presence of coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, is frequently disrupted in metabolic cardiomyopathy. This review explores the role of autophagy in the pathogenesis of high-fat diet (HFD) and streptozotocin (STZ)-induced metabolic cardiomyopathy, focusing on non-selective and selective autophagy pathways, including mitophagy, ER-phagy, and ferritinophagy. Key proteins and genes such as PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, and miR-34a are central to the regulation of autophagy in metabolic cardiomyopathy. Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, and drives fibrosis in the heart. Additionally, selective autophagy processes such as lipophagy, regulated by PNPLA8, and ferritinophagy, modulated by NCOA4, play pivotal roles in lipid metabolism and iron homeostasis. Emerging therapeutic strategies targeting autophagy, including plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds (e.g., sirtuin 3, LC3), and lipid/glucose-lowering drugs, offer promising avenues for mitigating the effects of metabolic cardiomyopathy. Despite recent advances, the precise mechanisms underlying autophagy in this context remain poorly understood. A deeper understanding of autophagy's regulatory networks, particularly involving these critical genes and proteins, may lead to novel therapeutic approaches for treating metabolic cardiomyopathy.
    Keywords:  ER-phagy; autophagy; ferritinophagy; high-fat diet (HFD); metabolic cardiomyopathy; streptozotocin (STZ)
    DOI:  https://doi.org/10.3390/ijms26041668
  8. J Mol Biol. 2025 Feb 22. pii: S0022-2836(25)00101-9. [Epub ahead of print] 169035
    Lysosomal degradation of ER client proteins by ER-phagy and related pathways.
    Carla Salomo-Coll, Natalia Jimenez-Moreno, Simon Wilkinson.
      The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation of overabundant, misfolded, aggregating or unwanted proteins is required to maintain proteostasis and avoid the deleterious consequences of aberrant protein accumulation, at a cellular and organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it is becoming clear that there is a substantial role for lysosomal degradation of "client" proteins from the ER lumen or membrane (ER-to-lysosome degradation, ERLAD). Here we provide a brief overview of the broad categories of ERLAD - predominantly ER-phagy (ER autophagy) pathways and related processes. We collate the client proteins known to date, either individual species or categories of proteins. Where known, we summarise the molecular mechanisms by which they are selected for degradation, and the setting in which lysosomal degradation of the client(s) is important for correct cell or tissue function. Finally, we highlight the questions that remain open in this area.
    DOI:  https://doi.org/10.1016/j.jmb.2025.169035
  9. Autophagy. 2025 Feb 24. 1-2
    Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.
    Tomokazu Murakawa, Kinya Otsu.
      In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the in vivo role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using bcl2l13 knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13S272A mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed bcl2l13 and prkn/parkin double-knockout mice but found no additive effects of prkn deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.Abbreviation: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.
    Keywords:  BCL2L13; heart failure; kinase; mitophagy; pressure overload
    DOI:  https://doi.org/10.1080/15548627.2025.2465408
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒02 at 1:14.