bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–10–04
ten papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Biophysical and molecular mechanisms of lysosomal mechanoresilience: Membrane tension, TMEM63A, and cellular injury.
  2. A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
  3. Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
  4. Lysosomal dysfunction in neurodegenerative disease.
  5. Integrative multi-omics analysis unveils the regulatory landscape of diabetic cardiomyopathy: from chromatin accessibility to transcript isoforms and epitranscriptome.
  6. Quantification of lipid sorting during clathrin-mediated endocytosis.
  7. Retraction Notice to: Lysosomal polyamine storage upon ATP13A2 loss impairs β-glucocerebrosidase via altered lysosomal pH and electrostatic hydrolase-lipid interactions.
  8. SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
  9. Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.
  10. Slow calcium removal contributes to impaired lusitropic response to β-adrenergic stimulation in HFpEF mice.
  1. Prog Biophys Mol Biol. 2026 Sep 28. pii: S0079-6107(26)00073-8. [Epub ahead of print]202 101956
    Biophysical and molecular mechanisms of lysosomal mechanoresilience: Membrane tension, TMEM63A, and cellular injury.
    Rabab S Hamad, Attalla F El-Kott, Sally Negm, Mohammed A AlShehri, Waleed Eltantawy, Elsayed A Elmorsy, Ebtehal M Abdel-Aal, Eman Hamza, Sameh Saber.
      Lysosomal membrane failure contributes to cellular injury by disrupting degradation, metabolism, immune signaling, and compartmental integrity, yet the physical principles that determine whether a mechanically loaded lysosome adapts or ruptures remain incompletely resolved. This review integrates biophysical and molecular evidence to examine lysosomal membrane tension as an organelle-state variable and TMEM63A as an emerging determinant of lysosomal mechanoresilience. We distinguish membrane tension from hydrostatic and osmotic pressure, organelle volume, membrane permeabilization, and rupture, and evaluate how surface-area-to-volume constraints, luminal solute accumulation, ion and water flux, membrane potential, lipid composition, and force-from-lipid gating shape mechanical failure thresholds. The strongest evidence comes from Drosophila TMEM63 and mouse TMEM63A lysosomal mechanosensitivity and macrophage models in which TMEM63A-dependent cation efflux lowers acute membrane tension and rupture susceptibility. Together, these findings support a pressure-relief model coupling mechanically activated conductance to lysosomal membrane stability. Evidence from lysosome-related organelles, lipid scrambling, myelination, infection, and pressure-sensitive mTORC1-TFEB/TFE3 signaling broadens the mechanistic scope without establishing a universal TMEM63A-dependent pathway. Accordingly, TMEM63A is best viewed as a system- and condition-dependent regulator of acute lysosomal mechanical vulnerability, not a general lysosomal controller or validated therapeutic target. Importantly, TMEM63A-linked disease phenotypes in humans and Tmem63a-deficient mice have not been causally linked to impaired lysosomal mechanoresilience, and the macrophage pressure-relief mechanism remains unvalidated in vivo. Resolving these uncertainties will require simultaneous, time-resolved measurements of tension, geometry, ion composition, membrane potential, permeability, and repair, combined with compartment-specific localization and rescue using wild-type, pore-defective, localization-defective, and disease-associated variants.
    Keywords:  Lysosomal membrane tension; Lysosomal rupture; Mechanosensitive ion channels; Membrane biophysics; Organelle mechanobiology; TMEM63A
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.101956
  2. Nature. 2026 Sep 30.
    A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
    Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.
      Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-026-11093-3
  3. Cell Rep. 2026 Oct 01. pii: S2211-1247(26)01144-7. [Epub ahead of print]45(10): 118065
    Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
    Chinmoy Sarkar, Yi Chen, Dexter Ph Nguyen, Mehari M Weldemariam, Yulemni Morel, Amir Mehrabani-Tabari, Nikki Gorny, Olivia Pettyjohn-Robin, Nivedita Hegdekar, Sagarina Thapa, Sazia Arefin Kachi, Sabrina Bustos, Stephanie Zalesak-Kravec, Christina Williams, Nicholas Leahy, Renee Ti Chou, Shilpa D Kumar, Carrie McCracken, Thomas A Blanpied, Mariusz Karbowski, Jace W Jones, Maureen A Kane, Michael P Cummings, Marta M Lipinski.
      Lipids dynamically reside in multiple intracellular locations, and their organellar distribution is important for function. During brain aging, lysosomal lipid changes have been noted, but lipid identity, interactions, and functional relevance have not been characterized. We used mass spectrometry to assess longitudinal changes in the lipidome and proteome of lysosomal fractions from the murine cortex, from 3 to 24 months, followed by multi-omics factor analysis (MOFA) to identify factors underlying lysosomal aging. Our data uncover an age-dependent increase in lysosomal abundance of lipid and protein myelin components and suggest altered sphingolipid catabolism favoring degradation of sphingomyelins over glycosphingolipids. We experimentally corroborate MOFA predictions to demonstrate that age-dependent accumulation of myelin-derived glycosphingolipids is associated with lysosomal enlargement and dysfunction and is most pronounced in microglia. Our findings suggest that age-related lysosomal lipidome changes resemble those observed in lysosomal storage diseases and underscore the importance of organelle-specific analyses for elucidating lipid function.
    Keywords:  CP: metabolism; CP: neuroscience; autophagy; brain aging; glycosphingolipids; lipid metabolism; lysosomes; mass spectrometry; microglia; multi-omics factor analysis (MOFA); myelin
    DOI:  https://doi.org/10.1016/j.celrep.2026.118065
  4. Nat Rev Neurol. 2026 Sep 29.
    Lysosomal dysfunction in neurodegenerative disease.
    Sarah M Brooker, Robert Coukos, Dimitri Krainc.
      Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.
    DOI:  https://doi.org/10.1038/s41582-026-01262-3
  5. Front Endocrinol (Lausanne). 2026 ;17 1928778
    Integrative multi-omics analysis unveils the regulatory landscape of diabetic cardiomyopathy: from chromatin accessibility to transcript isoforms and epitranscriptome.
    Licheng Ding, Kaiyuan Liu, Xiaofeng Ge, Zhaokai Li, Ke Hu, Shichen Bu.
      Diabetic cardiomyopathy (DCM) is a major contributor to heart failure in diabetic patients, characterized by profound metabolic remodeling and diastolic dysfunction. However, the multi-layered epitranscriptomic and post-transcriptional networks involved in this disease remain poorly understood. To address this, we established a type 2 diabetes-associated DCM mouse model using a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injections. By integrating single-molecule direct RNA sequencing (DRS-seq), chromatin accessibility profiling (ATAC-seq), and conventional bulk RNA-seq, we constructed a comprehensive epigenetic-transcriptional regulatory map of DCM. Using DRS-seq, we identified 21,156 full-length transcripts, including 8,457 (39.97%) novel unannotated isoforms, and observed a systemic 3'-UTR elongation under diabetic stress. Joint ATAC-seq and DRS-seq analysis identified concurrent reductions in promoter chromatin accessibility and transcript abundance for four genes, including Fam210b (mitochondrial iron homeostasis), Cdh22 (intercalated disc adhesion), Fbxo10 (ubiquitin-mediated RAGE degradation), and Cenpx (DNA double-strand break repair), suggesting a potential link between altered chromatin accessibility and transcriptional regulation in DCM. Additionally, DRS-seq revealed extensive alterations in the cardiac epitranscriptome, identifying 1,719 differential m6A sites and 3,146 differential m5C sites at single-molecule resolution. Among these epitranscriptomic changes, we observed a potential post-transcriptional interplay between m6A and alternative polyadenylation (APA). Furthermore, by applying the CIBERSORT algorithm to the DRS-seq dataset, we characterized the cardiac immune microenvironment, revealing distinct pathological remodeling defined by decreased plasma cells and Th1 cells alongside a specific increase in CD4+ memory T-cell infiltration. Pearson correlation analysis showed that, among the candidate genes, only the down-regulated mitochondrial regulator Fam210b exhibited a significant negative correlation with CD4+ memory T-cell infiltration, suggesting a potential molecular association between mitochondrial dysfunction and local adaptive immune changes. Together, our study provides a high-resolution landscape of the native cardiac transcriptome and epitranscriptome, highlighting epigenetic-transcriptional coupling, m6A-APA cooperative decay, and Fam210b-associated local immune microenvironment remodeling as potential pathogenic contributor, thus offering candidate therapeutic targets for diabetic heart failure.
    Keywords:  Fam210b; T-cell infiltration; diabetic cardiomyopathy; epitranscriptomics; multi-omics integration
    DOI:  https://doi.org/10.3389/fendo.2026.1928778
  6. Nat Cell Biol. 2026 Sep 29.
    Quantification of lipid sorting during clathrin-mediated endocytosis.
    H Mathilda Lennartz, Susana da Costa Nunes, Kristin Böhlig, Aditya Chhatre, Radek Šachl, Sascha M Kuhn, Lior Moneta, Pavel Barahtjan, Wan Yee Yau, Juan M Iglesias-Artola, Martin Hof, Lukáš Opálka, Carl D Modes, Alf Honigmann, André Nadler.
      Clathrin-mediated endocytosis is a major transport route for proteins from the plasma membrane to the interior of the cell. While the recruitment of cargo proteins to clathrin-coated pits is well understood, it remains an open question whether lipids are also sorted by this process. Here, to address this question, we combined super-resolution stimulated emission depletion imaging of bifunctional lipid probes with mathematical modelling. Quantification of ten different lipid species revealed significant differences in pit partitioning, ranging from slight enrichment to moderate exclusion. We find that the lipid asymmetry in the plasma membrane is sufficient to explain the observed trend. Taken together, our findings imply that clathrin-mediated endocytosis has a minor selectivity for cytoplasmic leaflet lipids, but overall does not substantially contribute to lipid sorting compared with non-vesicular trafficking.
    DOI:  https://doi.org/10.1038/s41556-026-02068-7
  7. Cell Rep. 2026 09 28. pii: S2211-1247(26)01206-4. [Epub ahead of print]45(10): 118127
    Retraction Notice to: Lysosomal polyamine storage upon ATP13A2 loss impairs β-glucocerebrosidase via altered lysosomal pH and electrostatic hydrolase-lipid interactions.
    Madhuja Samaddar, Gabriel A Fitzgerald, Ann Hong Nguyen, Sonnet S Davis, Shourya Jain, Jian Guo, Nicholas E Propson, Bettina van Lengerich, Yajuan Shi, Srijana Balasundar, Lionel Rougé, Jamal Alkabsh, Anil Rana, Julie Yi, Marcus Y Chin, Isabel A Becerra, Annie Arguello, Brian M Fox, Todd Logan, Jung H Suh, Anastasia G Henry, Gilbert Di Paolo.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.118127
  8. Nat Commun. 2026 09 11. pii: 10407. [Epub ahead of print]17(1):
    SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
    Ke Hu, Yin-Hu Wang, Anthony Y Tao, Maxwell McDermott, Miki Jishage, Li Zhong, Thomas Boehringer, Marcus J Hines, Sergei B Koralov, Ebbe Boedtkjer, Stefan Feske.
      Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na+/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection. Mechanistically, SLC4A7 deletion results in intracellular acidification and lysosomal alkalinization, and is associated with impaired function of the mechanistic target of rapamycin complex 1 (mTORC1). Enforcing mTORC1 activation in SLC4A7-deficient B cells or B cells in which intracellular pH is acidified by blocking Na+/H+ exchanger (NHE) function restores PB differentiation in vitro. Moreover, ASC differentiation and antibody responses are impaired under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Altogether, we identify a critical relationship between intracellular pH regulation through SLC4A7 and mTORC1-dependent ASC differentiation and humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-026-77588-9
  9. EMBO Rep. 2026 Oct 02.
    Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.
    Hiroshi Hanafusa, Kota Ohashi, Hiromu Shojima, Yurika Honda, Naoki Hisamoto, Takeshi Kameyama, Muneaki Miyata, Kiyohito Mizutani, Yoshimi Takai, Kunihiro Matsumoto.
      Parkinson's disease (PD) and related synucleinopathies are marked by the accumulation and propagation of α-synuclein (α-syn) aggregates, a process primarily studied in neurons. Whether astrocytes actively contribute to α-syn processing and intercellular transfer remains unclear. Here, using a physiologically relevant neuron-astrocyte co-culture system that recapitulates tripartite synapse architecture, we show that astrocytes process α-syn and influence the morphological maturation of neuronal aggregates. Astrocytes internalize α-syn pre-formed fibrils (PFFs) and generate C-terminally truncated α-syn species via a Cathepsin D (CtsD)-dependent process. PFF-loaded astrocytes transfer α-syn-containing material to neurons and promote the formation and maturation of pS129-α-syn-positive Lewy neurite (LN)-like aggregates. Notably, α-syn PFF exposure induces lysosomal membrane damage, a senescence-like reactive state, and CtsD upregulation in astrocytes. Although PFF-containing lysosomes undergo autophagic engulfment, they persist within astrocytes, and a subset is detected beyond the astrocytic membrane boundary. Together, our findings support a model in which astrocytic lysosomal remodeling of internalized α-syn contributes to the morphological maturation and intercellular propagation of neuronal α-syn pathology in this co-culture system.
    DOI:  https://doi.org/10.1038/s44319-026-00927-w
  10. J Physiol. 2026 Sep 30.
    Slow calcium removal contributes to impaired lusitropic response to β-adrenergic stimulation in HFpEF mice.
    Tamzin Zawadzki, Diana S Usai, Sif G Kaad, Katrine H Rasmussen, Mie S Larsen, Jens C B Jacobsen, Morten B Thomsen.
      Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms remain incompletely understood and effective therapies are lacking. Diastolic dysfunction, a hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca2+) handling remains unclear. This study aimed to document impaired lusitropy and diastolic dysfunction in HFpEF, and to determine the contribution of altered ventricular Ca2+ handling to slowed myocardial relaxation. HFpEF was induced by diet-driven obesity and hypertension. Cardiac function was assessed in vivo by echocardiography, ex vivo in preload-controlled isolated hearts and at the cellular level by Ca2+ imaging of isolated ventricular myocytes. HFpEF mice developed diastolic dysfunction, hypertrophy, reduced cardiac output and exercise intolerance, yet ejection fraction was preserved. Impaired lusitropy was evident in vivo, ex vivo and at the cellular level, where basal cytosolic Ca2+ handling was preserved, but the β-adrenergic-recruitable acceleration of Ca2+ clearance was impaired. This attenuated lusitropic response to β-adrenergic stimulation in HFpEF myocytes was mirrored in vivo during echocardiography. Slowed myocardial relaxation is a consistent feature of HFpEF, evident at the organ, tissue and cellular levels. β-Adrenergic stimulation normally enhances lusitropy, but this response is blunted in HFpEF hearts both in vivo and in isolated cardiomyocytes. Impaired β-adrenergic amplification of Ca2+ removal is associated with slowed ventricular relaxation, reduced cardiac output and exercise intolerance in HFpEF, identifying defective lusitropic reserve as a potential therapeutic target. KEY POINTS: Heart failure with preserved ejection fraction (HFpEF) lacks effective therapies, in part because the disease mechanisms remain incompletely defined. Using a mouse model combining obesity and hypertension, we demonstrate diastolic dysfunction, reduced cardiac output and exercise intolerance despite preserved ejection fraction. Ventricular relaxation was impaired in HFpEF mice in vivo and ex vivo. β-Adrenergic lusitropic reserve was reduced in HFpEF mice during ultrasound echocardiography, which was mirrored by a blunted β-adrenergic acceleration of cytosolic Ca2+ removal in disaggregated cells from HFpEF hearts. These findings identify defective myocyte Ca2+ handling as a distinct mechanistic contributor to HFpEF pathophysiology and suggest that therapeutic strategies aimed at restoring Ca2+ removal and lusitropic reserve may improve diastolic performance and functional capacity in HFpEF patients.
    Keywords:  Diastolic dysfunction; excitation–contraction coupling; lusitropy; ventricular myocyte; β‐adrenergic signalling
    DOI:  https://doi.org/10.1113/JP291587
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