bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–10–19
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Visualization of lysosomal membrane proteins by cryo electron tomography.
  2. Proteomics Insights Into Lysosome Biogenesis and Maturation.
  3. Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction.
  4. Vesicular transport in the autophagic route: RAB GTPases as pivotal regulators of autophagy.
  5. The Cardioprotective Effects of Adiponectin in Diabetes.
  6. Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.
  7. Lysosomal Ca2+ Release Through TRPML1 Governs Ventricular Arrhythmia After Myocardial Infarction.
  1. Nat Commun. 2025 Oct 17. 16(1): 9234
    Visualization of lysosomal membrane proteins by cryo electron tomography.
    Bridget M McVeigh, José J De Jesús-Pérez, Dirk H Siepe, Prerana Gogoi, Shrawan Kumar Mageswaran, Marian Kalocsay, Elaine M Mihelc, Vera Y Moiseenkova-Bell.
      Lysosomes are essential organelles for cellular homeostasis and signaling, with dysfunction linked to neurological disorders, lysosomal storage diseases, and cancer. While proteomics has advanced our understanding of lysosomal composition, the structural characterization of lysosomal membrane proteins in their native environment remains a significant challenge. Here, we developed a cryo electron tomography workflow to visualize lysosomal membrane proteins within intact, native lysosomal membranes. We isolated endolysosomes by independently targeting two lysosomal membrane proteins, transient receptor potential mucolipin 1 and transmembrane protein 192, enriching organelles that exhibited the expected morphology and proteomic composition of the endolysosomal system. Sub-tomogram averaging enabled the structural refinement of key membrane and membrane-associated proteins, including V-ATPase, Flotillin, and Clathrin, directly within the lysosomal membrane, revealing their heterogeneous distribution across endolysosomal organelles. By integrating proteomics with structural biology, our workflow establishes a powerful platform for studying lysosomal membrane protein function in health and disease, paving the way for future discoveries in membrane-associated lysosomal mechanisms.
    DOI:  https://doi.org/10.1038/s41467-025-64314-0
  2. Proteomics. 2025 Oct 15. e70058
    Proteomics Insights Into Lysosome Biogenesis and Maturation.
    Katharina Hirn, Sofía Fajardo-Callejón, Dominic Winter.
      Lysosomes constitute the main degradative organelle of most eukaryotic cells and are capable of breaking down a wide spectrum of biomolecules, including proteins, lipids, glycans, and DNA/RNA. They play crucial roles in the regulation of cellular homeostasis, acting as metabolic signaling centers for the correlation of nutrient availability and biosynthetic processes. The lysosome's importance is highlighted by several human diseases associated with its dysfunction, including both early- and late-onset conditions, dependent on the level of functional impairment. Lysosomal biogenesis presents a multi-step process consisting of various delivery routes for its individual constituents, enabling strict activity control of the currently known ∼60 lysosomal hydrolases to prevent cellular self-digestion and proper assembly of the lysosomal membrane. In this review, we recapitulate the contribution of mass spectrometry (MS)-based proteomics to the characterization of lysosomal biogenesis in the last two decades. The enrichment and proteomic analysis of lysosomes and lysosomal proteins played an invaluable role for the investigation of lysosomes, encompassing the control of lysosomal gene expression, the characterization of sorting/trafficking processes, and the assignment of lysosomal proteins. This has resulted so far in the definition of ∼350 proteins which have been identified to be located in/at lysosomes or are of crucial importance for their function.
    Keywords:  biogenesis; lysosomal proteins; lysosome; mass spectrometry; maturation; protein trafficking; proteomics; vesicular transport
    DOI:  https://doi.org/10.1002/pmic.70058
  3. Autophagy. 2025 Oct 16.
    Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction.
    Einar K Krogsaeter, Justin McKetney, Leopoldo Valiente-Banuet, Angelica Marquez, Alexandra Willis, Zeynep Cakir, Erica Stevenson, Gwendolyn M Jang, Antara Rao, Emmy Li, Anton Zhou, Anjani Attili, Timothy S Chang, Martin Kampmann, Yadong Huang, Nevan J Krogan, Danielle L Swaney.
      APOE4 is the primary risk factor for Alzheimer disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that APOE4 localizes to lysosomes, the influence of APOE4 on lysosomal function remains unexplored. We find that expression of APOE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function. To identify driving factors for these defects, we performed quantitative lysosomal proteome profiling. This revealed that APOE4 expression results in differential regulation of numerous lysosomal proteins, correlating with APOE allele status and disease severity in AD brains. In particular, APOE4 expression results in the depletion of lysosomal LGALS3BP and the accumulation of lysosomal TMED5. We additionally validated that these lysosomal protein changes can be targeted to modulate lysosomal function. Taken together, this work thereby reveals that APOE4 causes widespread lysosomal defects through remodeling the lysosomal proteome, with the lysosomal TMED5 accumulation and LGALS3BP depletion manifesting as lysosomal alkalinization in APOE4 neurons.
    Keywords:  APOE4; Alzheimer disease; LGALS3BP; LysoIP; TMED5; lysosomes; pH
    DOI:  https://doi.org/10.1080/15548627.2025.2576613
  4. Biochem J. 2025 Oct 17. 482(20): 1531-1544
    Vesicular transport in the autophagic route: RAB GTPases as pivotal regulators of autophagy.
    Romina Abba, María Isabel Colombo.
      Autophagy is recognized as one of the two main intracellular recycling pathways that play an essential role in cellular homeostasis by maintaining accurate energy levels and carrying out quality control functions. One of the major autophagic mechanisms, the so-called macroautophagy, is involved in the lysosomal degradation of different cytoplasmic components, such as long-lived proteins and damaged or dysfunctional organelles. Numerous studies have demonstrated that participation of intracellular membrane trafficking events is key for the progression of autophagy. In this review, we will focus on the small GTPases of the RAS-related in brain protein family, which have a crucial role in vesicular transport.
    Keywords:  RAB GTPases; autophagy; membrane traffic
    DOI:  https://doi.org/10.1042/BCJ20253092
  5. Curr Diab Rep. 2025 Oct 13. 25(1): 53
    The Cardioprotective Effects of Adiponectin in Diabetes.
    Tara Kazemi, Yuanjie Mao, Tina Zhang.
       PURPOSE OF REVIEW: Adiponectin, a hormone secreted by adipocytes, plays a crucial role in maintaining metabolic balance and supporting cardiovascular health. Although it is known for its protective effects, such as improving insulin sensitivity, reducing inflammation, and maintaining endothelial function, there are paradoxical associations between high adiponectin levels and increased cardiovascular mortality-referred to as the "adiponectin paradox"-which complicates its clinical interpretation. This review explores the cardioprotective effects of adiponectin in both type 1 and type 2 diabetes, focusing on its potential to regulate glucose metabolism and prevent cardiovascular complications.
    RECENT FINDINGS: By reviewing key studies, the article evaluates adiponectin's diverse roles and compares its effects on cardiovascular outcomes across diabetes subtypes, especially in diabetic cardiomyopathy, with an emphasis on congestive heart failure. The findings underscore the importance of further research into therapeutic strategies aimed at modulating adiponectin levels, particularly for individuals with diabetes and congestive heart failure. Understanding the dual nature of adiponectin's effects is critical for developing target interventions to improve cardiovascular outcomes in diabetic populations.
    Keywords:  Adiponectin; Complications; Congestive heart failure; Diabetes mellitus
    DOI:  https://doi.org/10.1007/s11892-025-01610-5
  6. Life Sci Alliance. 2026 Jan;pii: e202403020. [Epub ahead of print]9(1):
    Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.
    Anjali Vishwakarma, Lilia Chihki, Kiran Todkar, Mathieu Ouellet, Marc Germain.
      Mitochondria are essential for bioenergetics and cellular processes including cell differentiation and immunity; alterations in these processes cause a wide range of muscular and neurological pathologies. Although these pathologies have traditionally been associated with ATP deficits, mitochondrial dysfunction also leads to reactive oxygen species (ROS) generation, inflammation, and alterations in the function of other organelles. Although the negative impact of mitochondrial dysfunction on lysosomal activity is established, the relationship between mitochondria and the rest of the endocytic compartment remains poorly understood. Here, we show that inhibiting mitochondrial activity through genetic and chemical approaches causes early endosome (EE) perinuclear aggregation and impairs cargo delivery to lysosomes. This impairment is due to ROS-mediated alterations in microtubule architecture and centrosome dynamics. Antioxidants can rescue these EE defects, underlying the pivotal role of mitochondria in maintaining cellular activities through ROS regulation of microtubule networks. Our findings highlight the significance of mitochondria beyond ATP production, emphasizing their critical involvement in endocytic trafficking and cellular homeostasis. These insights emphasize mitochondria's critical involvement in cellular activities and suggest novel targets for therapies to mitigate the effects of mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202403020
  7. Circ Arrhythm Electrophysiol. 2025 Oct 14. e013964
    Lysosomal Ca2+ Release Through TRPML1 Governs Ventricular Arrhythmia After Myocardial Infarction.
    An Xie, Gyeoung-Jin Kang, Hong Liu, Eun Ji Kim, Feng Feng, Dobromir Dobrev, Samuel C Dudley.
       BACKGROUND: In nonischemic cardiomyopathy, mitochondrial Ca2+ handling is involved in arrhythmogenesis by modulating diastolic sarcoplasmic reticulum (SR) Ca2+ release. Recently, it has been reported that lysosomal Ca2+ release can trigger an SR Ca2+ release. We investigated whether lysosomal Ca2+ flux through the TRPML1 (transient receptor potential mucolipin 1) channel could contribute to ischemic cardiomyopathy-related arrhythmia by causing diastolic SR Ca2+ release.
    METHODS: Ischemic cardiomyopathy was induced in wild-type C57BL/6J and TRPML1 heterozygous knockdown (TRPML1±) mice by ligating the left anterior descending coronary artery. Mice were studied at 3 weeks after myocardial infarction (MI).
    RESULTS: After MI, the lysosomal-restricted TRPML1 Ca2+ release channel was significantly increased in human patients with ischemic or nonischemic cardiomyopathy. TRPML1, but not the TPC2 (2-pore channel 2), was significantly upregulated by 85% in the mouse MI border zone and by 55% in a remote zone. Lysosomal number and approximation to the SR were increased after MI. Lysosomal Ca2+ release was substantially upregulated in MI mouse cardiomyocytes compared with sham cardiomyocytes. The action potential duration was prolonged, and arrhythmogenic diastolic SR Ca2+ release was increased in the cardiomyocytes isolated from MI mice. Blocking TRPML1 reduced action potential duration prolongation and depressed early and delayed afterdepolarizations in cardiomyocytes isolated from MI mice, while the TRPML1 agonist increased TRPML1-dependent cellular triggered activity. A TRPML1 antagonist could inhibit induced ventricular fibrillation in MI mice. Consistent with that result, genetic knockdown of TRPML1 could inhibit arrhythmic risk after MI. The effects of TRPML1-targeted drugs were not seen in control cardiomyocytes.
    CONCLUSIONS: Lysosomes contribute to arrhythmic risk after MI because of increased number, proximity to the SR, and induction of diastolic SR Ca2+ release mediated by TRPML1-dependent lysosomal Ca2+ release.
    Keywords:  arrhythmias, cardiac; calcium; lysosomes; myocardial infarction; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCEP.125.013964
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