bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–08–02
twelve papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Signatures of aging and disease in a single organelle.
  2. TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
  3. Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities.
  4. Subcellular Regulation of Ferroptosis: Roles of Individual Intracellular Organelles and Crosstalk.
  5. The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.
  6. STING Goes Mitochondrial: A Metabolic Regulator in Diabetic Cardiomyopathy.
  7. Approaches to Organelle Spacing at Membrane Contact Sites.
  8. Nanoscale biointerfaces in inter-organelle communication: membrane contact sites, organelle trafficking, and cell fate control.
  9. Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
  10. SLC26A11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport.
  11. The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
  12. SGLT2 Inhibitors as Modulators of Mitochondrial Ion Transport and ER-Mitochondria Crosstalk in Diabetic Cardiomyopathy.
  1. Science. 2026 Jul 30. 393(6810): 461
    Signatures of aging and disease in a single organelle.
    Jeeyoon Na, Anne Brunet.
      Changes in lysosomal metabolites are associated with both aging organs and lysosomal storage diseases.
    DOI:  https://doi.org/10.1126/science.aej5901
  2. Circ Res. 2026 Jul 31. 139(4): e329311
    TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
    Ivor J Benjamin, Jacek Zielonka.
      
    Keywords:  Editorials; heart failure; lysosomes; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329311
  3. Biochim Biophys Acta Rev Cancer. 2026 Jul 25. pii: S0304-419X(26)00141-1. [Epub ahead of print] 189669
    Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities.
    Amruta Singh, Soumyadip Sinha, Prakash Kumar Senapati, Kewal Kumar Mahapatra, Sujit Kumar Bhutia.
      Lysosomes are vital organelles that maintain cellular homeostasis and orchestrate dynamic adaptations during physiological and pathological stress. Lysosomal damage, caused by various extrinsic and intrinsic factors, impairs its integrity and simultaneously disrupts the normal functioning of other organelles, including the endoplasmic reticulum and mitochondria. Lysosomal homeostasis through the lysosomal stress response (LSR) network aids cells in adapting to organelle damage, nutrient fluctuations, oxidative stress, and metabolic irregularities. This coordinated network is primarily governed by proteins, including mTOR, TFEB/TFE3, AMPK, Rag GTPases, Ragulator, and TRPML1, which integrates mechanisms involving rapid lysosomal membrane repair, selective elimination of extensively damaged lysosomes, de novo lysosomal biogenesis, and lysosomal reformation pathways. Dysregulation of the LSR network leads to different types of diseases, including cancer. This review summarizes the current understanding of lysosomal damage mitigation, particularly in cancer, where remodeling of the LSR network not only enables cancer cells to maintain metabolic plasticity by resisting therapeutic stress and promoting malignancy but also identifies the LSR network as a critical determinant in tumorigenesis. We further provide a detailed discussion of emerging evidence on the disruption of lysosomal homeostasis, highlighting strong links between lysosome-targeting drugs and cancer therapeutics. Altogether, we establish the LSR network as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.
    Keywords:  Cancer; Lysosomal damage; Lysosomal homeostasis; Lysosomal stress response (LSR) network
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189669
  4. Am J Physiol Cell Physiol. 2026 Jul 29.
    Subcellular Regulation of Ferroptosis: Roles of Individual Intracellular Organelles and Crosstalk.
    Chanon Piamsiri, Judith K Gwathmey, Lai-Hua Xie.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Emerging evidence indicates that susceptibility to ferroptosis is not governed solely by cytosolic signaling pathways, but instead results from the coordinated actions of multiple intracellular organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), and lipid droplets. Mitochondria play dual roles in ferroptosis by integrating metabolic activity, redox balance, and mitochondrial quality control; thereby influencing reactive oxygen species generation and lipid peroxidation. Lysosomes regulate ferroptotic sensitivity through iron mobilization, inter-organelle iron transfer, lysosomal redox activity/lipid peroxidation, lysosomal signaling hub, and ferritinophagy. The ER contributes to ferroptosis by coordinating lipid biosynthesis, membrane polyunsaturated fatty acid composition, and unfolded protein response signaling, as well as by disrupting antioxidant defenses and iron homeostasis, especially during ER stress. Lipid droplets function as dynamic lipid reservoirs that buffer oxidizable fatty acids or, upon mobilization, supply substrates that fuel ferroptosis-associated lipid peroxidation. Here, we provide a comprehensive review of current mechanistic insights and recent advances in organelle-specific regulation and inter-organelle crosstalk during ferroptosis, highlighting emerging therapeutic opportunities and key experimental challenges. An integrated understanding of this multi-organelle regulatory network is essential for modulating ferroptosis in human diseases.
    Keywords:  Endoplasmic/Sarcoplasmic Reticulum; Ferroptosis; Lipid droplet; Lysosome; Mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00334.2026
  5. Front Cell Dev Biol. 2026 ;14 1860821
    The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.
    Yao Du, Li Li, Mingtao Du, Zhi Xu, Xiaorong Zhang, Wa Cao.
      The endo-lysosomal system is a central regulator of intracellular trafficking, cargo degradation, and metabolic homeostasis. Its dynamic function is closely intertwined with lipid metabolism, forming an integrated regulatory network termed the endo-lysosomal-lipid axis. Disruption of this axis can impair endosomal maturation, lysosomal acidification, autophagic degradation, and lysosome-centered signaling pathways, resulting in defective cellular clearance and chronic inflammatory responses. Conversely, dysfunction of the endo-lysosomal system disrupts cholesterol trafficking, lipid redistribution, and macromolecular degradation, ultimately promoting secondary lipid accumulation and metabolic imbalance. In this review, we summarize the reciprocal interactions between lipid metabolism and endo-lysosomal function, with particular emphasis on membrane trafficking, lysosomal homeostasis, autophagy, membrane contact sites, and multicellular lipid clearance networks. We further discuss how these interconnected processes contribute to disease progression and highlight emerging therapeutic strategies aimed at restoring lysosomal function and lipid homeostasis. Understanding the dynamic regulation of the endo-lysosomal-lipid axis may provide new mechanistic insights into metabolic and neurodegenerative disorders and identify novel therapeutic opportunities.
    Keywords:  autophagy; cholesterol trafficking; endo-lysosomal system; endo-lysosomal–lipid axis; lipid metabolism; lysosomal dysfunction; metabolic disease
    DOI:  https://doi.org/10.3389/fcell.2026.1860821
  6. Circ Res. 2026 Jul 31. 139(4): e329116
    STING Goes Mitochondrial: A Metabolic Regulator in Diabetic Cardiomyopathy.
    Giulia Guerra, Alessandra Ghigo.
      
    Keywords:  Editorials; diabetic cardiomyopathies; heart failure; immunity, innate; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329116
  7. Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261473365
    Approaches to Organelle Spacing at Membrane Contact Sites.
    Tomas Knedlik, Federica Dal Bello, Marta Giacomello.
      Membrane contact sites (MCSs) are points where organelle surfaces are juxtaposed, without fusion of their membranes. Research in the MCS field has widely focused on the molecules and mechanisms that hold organelles together, known as "tethers", based on the correct presumption that processes mediated by MCSs depend on their spatial proximity. However, it has become clear that the distance between the membranes also have a biological role, particularly in processes such as Ca2+ transfer, while its relevance for other functions, such as lipid exchange, remains less clear. This supports the idea that there may be molecules that keep membranes apart, referred to as "spacers". While some evidence supports this hypothesis, the mechanisms of spacing remain unclear. In this opinion article, we briefly describe three potential spacing mechanisms that we have hypothesised based on direct and indirect experimental evidence. Briefly, we propose the existence of different types of organelle spacing approaches (OSAs) that result in organelle distancing: first, the presence of rod-like spacing molecules; second, the removal of some tethers, achieved through their masking, dissociation from MCSs, or degradation, which could result either in complete untethering of the organelles or in variations in the distance between them due to changes in the composition of the MCSs; third, cytoskeleton-mediated pulling forces that can increase the distance between the two apposing membranes. Our aim is to stimulate discussion and initiate debate on the importance of maintaining the correct distance between organelles.
    Keywords:  contact; membrane; organelle; signaling(signalling); tether
    DOI:  https://doi.org/10.1177/25152564261473365
  8. Front Cell Dev Biol. 2026 ;14 1901757
    Nanoscale biointerfaces in inter-organelle communication: membrane contact sites, organelle trafficking, and cell fate control.
    Mohamed R Abdel-Hamed, Sameh Saber, Elsayed A Elmorsy, Basem H Elesawy, Maha M Amer, Abdel-Moneim Hafez Abdel-Moneim, Alaa El-Din L Firgany, Enas A Mohamed, Huda Eltayeb, Ageeb M Hassan, Mohamed El-Sayed, Ahmed Y Kira.
      Cellular and tissue organization depends on the spatial arrangement, ultrastructure, and functional coupling of organelles. This review reframes intracellular nanomaterials as nanoscale tools for interrogating and modulating membrane contact sites (MCSs), rather than simply as delivery systems. We focus on mitochondria, the endoplasmic reticulum, lysosomes, endosomes, and the nucleus because these compartments form dynamic contact networks that regulate metabolism, calcium and redox signaling, membrane trafficking, autophagy, mitophagy, chromatin organization, stress adaptation, and cell fate. Emphasis is placed on morphological and ultrastructural readouts, including mitochondrial cristae organization, fission-fusion balance, membrane-potential-dependent localization, endosomal and lysosomal trafficking, ER-mitochondria and lysosome-mitochondria communication, nuclear-pore access, chromatin organization, and inter-organelle contact-site remodeling. We discuss how particle size, surface charge, geometry, ligand presentation, and stimulus-responsive behavior influence cellular uptake, endosomal escape, organelle localization, and structural consequences within cells and tissues. A central distinction is made between intentional organelle nano-regulation, in which engineered systems are designed to engage defined subcellular mechanisms and organelle interfaces, and incidental stress responses, in which altered morphology or gene expression reflects oxidative, lysosomal, mitochondrial, inflammatory, or genotoxic injury. By organizing current evidence around MCS biology, subcellular compartmentalization, membrane trafficking, organelle dynamics, and tissue-relevant cell fate decisions, this review provides a morphology-centered framework for evaluating intracellular nanomaterials in health, disease, stem-cell biology, and regenerative bioengineering.
    Keywords:  ER–mitochondria crosstalk; cell fate regulation; endolysosomal trafficking; inter-organelle communication; membrane contact sites; organelle-targeted nanomaterials
    DOI:  https://doi.org/10.3389/fcell.2026.1901757
  9. Science. 2026 Jul 30. 393(6810): eady0832
    Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    DOI:  https://doi.org/10.1126/science.ady0832
  10. Nat Commun. 2026 07 27. pii: 7407. [Epub ahead of print]17(1):
    SLC26A11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport.
    Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanqa T Hove, Stefanie Bungert-Plümke, Bettina Böttcher, Jan-Philipp Machtens, Christoph Fahlke, Eric R Geertsma.
      Membrane transporters and channels are generally assumed to be based on distinct structural and functional principles. SLC26A11, a solute carrier with high expression levels in the brain, has been proposed to function as either an anion transporter or a channel. Here, we resolve this apparent discrepancy by demonstrating that SLC26A11 is a dual-function protein capable of operating as both a sulfate transporter and a chloride channel. By resolving its structure and combining biochemical studies and molecular dynamics simulations, we show that SLC26A11 exhibits all the hallmarks of a secondary transporter. The mechanistic basis for its selective ion transport identifies the protein as the elusive lysosomal sulfate exporter. Additionally, we demonstrate that SLC26A11 exhibits an uncoupled, channel-like chloride conductance gated by proton:sulfate symport. Our finding that the chloride-conducting state arises from the transport cycle may contribute to the development of therapeutic strategies for treating brain edema, and the identification of its role in lysosome sulfate efflux may provide new approaches to study and treat lysosomal storage diseases.
    DOI:  https://doi.org/10.1038/s41467-026-75749-4
  11. J Cell Sci. 2026 Jul 15. pii: jcs265083. [Epub ahead of print]139(14):
    The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
    Rebecca Morrison, Simeon R Mihaylov, Chak Hon Luk, Cyril Lemerle, Angela Rodgers, Natalia Athanasiadi, Huw R Morris, Enrica Pellegrino, Sila K Ultanir, Maximiliano G Gutierrez.
      Variants in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, yet how these variants alter immune cell function remains unclear. Because LRRK2 is activated by lysosomal damage in macrophages, we investigated how the pathogenic G2019S variant affects macrophage responses to lysosomal damage. Here, we show that LRRK2 G2019S has an effect during lysosomal damage through kinase-dependent and kinase-independent mechanisms. Phosphoproteomic analysis revealed that lysosomal damage induces selective rewiring of LRRK2-dependent Rab GTPase phosphorylation, characterised by increased Rab12 phosphorylation and reduced Rab35 phosphorylation without global kinase hyperactivation. Strikingly, LRRK2 G2019S macrophages showed increased susceptibility to apoptosis following lysosomal damage. This increase in cell death occurred independently of the kinase activity, indicating a distinct kinase-independent role of LRRK2 in regulating cell survival. We generated isogenic induced pluripotent stem cells from patients carrying the LRRK2 G2019S variant and confirmed that LRRK2 G2019S macrophages are more susceptible to cell death in a kinase-independent manner. Together, our findings support a model in which the LRRK2 G2019S variant selectively changes the phosphorylation of Rab GTPases in macrophages and increases cell death after lysosomal damage in macrophages.
    Keywords:  Apoptosis; LRRK2; Lysosomal damage; Macrophage; Parkinson's disease; Rab GTPase
    DOI:  https://doi.org/10.1242/jcs.265083
  12. Am J Physiol Cell Physiol. 2026 Jul 29.
    SGLT2 Inhibitors as Modulators of Mitochondrial Ion Transport and ER-Mitochondria Crosstalk in Diabetic Cardiomyopathy.
    Jessa Flores, Maria Victoria Faith Garcia, Prycelline Abedejos, Jed Allyn Hernandez, Trong Kha Pham, Hyoung Kyu Kim, Jubert Marquez, Jin Han.
      Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus and a leading contributor to heart failure. A central feature of DCM is the disruption of mitochondrial bioenergetics and calcium homeostasis, processes that are tightly regulated through mitochondria-associated endoplasmic reticulum membranes (MAMs). These ER-mitochondria contact sites coordinate mitochondrial ion transport systems, including the mitochondrial calcium uniporter (MCU), Na⁺/Ca²⁺ exchanger (NCLX), and potassium channels, which collectively govern mitochondrial metabolism, redox balance, and cell survival.
    Keywords:  diabetic cardiomyopathy; endoplasmic reticulum stress; mitochondria; mitochondrial channels; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1152/ajpcell.00230.2026
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒02 at 12:56.