bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–02–22
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Lysosome pH Dynamics in Physiology and Disease: Molecular Mechanisms and Therapeutic Insights.
  2. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
  3. Cardiac-restricted Nrf2 activation blocks diabetic cardiomyopathy via Akt-driven glycolysis and AMPK-PGC-1α fatty-acid oxidation.
  4. Lysosome trafficking across intracellular and intercellular networks in the brain.
  5. Angiotensin-(1-9) attenuates diabetic cardiomyopathy by improving insulin resistance.
  6. Lysosome-targeting chimeras enable targeted protein degradation.
  7. Repurposing metformin for cardioprotection: mechanisms and therapeutic potential across cardiovascular pathologies.
  8. Adaptor-mediated recruitment of three dyneins to dynactin enhances force generation.
  9. Type 2 Diabetes disrupts T-tubule and RyR2 organisation in male but not female rat ventricular muscle.
  1. Acta Physiol (Oxf). 2026 Mar;242(3): e70160
    Lysosome pH Dynamics in Physiology and Disease: Molecular Mechanisms and Therapeutic Insights.
    Sonia Infante-Tadeo, Diane L Barber.
       BACKGROUND: An acidic lysosomal lumen (pH ~4.5) is essential for the degradative and signaling functions of this organelle, which serves as a central hub for cellular homeostasis. Lysosome pH (pHlys), however, is not static but dynamically regulated by the coordinated action of the V-ATPase, counterion fluxes, membrane composition, and nutrient-sensitive signaling networks.
    PURPOSE: This review integrates recent advances in the molecular mechanisms regulating pHlys with emerging insights on how dysregulated pHlys contributes to pathologies in neurodegenerative disorders, lysosomal storage diseases, and cancers with changes in lumenal proteolytic activity and macromolecular degradation.
    MAIN FINDINGS: We discuss how pHlys acts as both a sensor and effector in lysosome biology, shaping transcriptional responses, membrane trafficking, and stress adaptation. We also review tools to measure pHlys, ranging from fluorescent dyes to genetically encoded biosensors and nanomaterial-based probes, and evaluate their use in disease-modeling applications.
    CONCLUSIONS: By highlighting pHlys as a nodal point in cellular functions, this review underscores the relevance of pHlys as a diagnostic marker and therapeutic target. Restoring pHlys in diseases offers translational potential to re-establish proteostasis and limit associated pathologies.
    Keywords:  cancer; lysosomal signaling; lysosome pH; neurodegeneration; pHlys regulation
    DOI:  https://doi.org/10.1111/apha.70160
  2. Dev Cell. 2026 Feb 17. pii: S1534-5807(26)00037-7. [Epub ahead of print]
    Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
    Jyotirekha Das, Saloni K Hombalkar, Alison D Klein, Esraa Nsasra, Muskaan Vasandani, Kay Petruzzi, Dajun Lu, Stephen Ruiz, Orit Kliper-Gross, Jiachen Hu, Michelle Riegman, Xuejun Jiang, Daniel A Heller, Assaf Zaritsky, Michelle S Bradbury, Michael Overholtzer.
      Ferroptosis is a lipid peroxide-dependent form of cell death that occurs in degenerative conditions and may be leveraged for cancer therapy. Although numerous regulators are known to control its cell-autonomous execution, ferroptosis also has a collective property that involves propagation between cells, and this regulation has remained more obscure. Different modes of ferroptosis induction involving inhibition of the anti-ferroptotic enzyme GPX4 or depletion of glutathione can impact the collective death response differently, but the mechanisms underlying "single-cell" versus "propagative" ferroptosis are not well understood. Here, we discover significant lysosome rupture occurring during propagative ferroptosis and identify glutathione depletion as sufficient to convert GPX4 inhibition from an individual-cell response to a collective response. We find that induction of single-cell ferroptosis involves heterogeneous death profiles, with necrosis and apoptosis occurring in parallel within cell populations. These findings identify factors that control propagation and underscore lysosomes as critical to the execution of ferroptosis.
    Keywords:  GPX4; TFEB; apoptosis; cathepsin; ferroptosis; iron; lipid peroxidation; lysosome; necrosis; propagation
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.014
  3. Acta Diabetol. 2026 Feb 18.
    Cardiac-restricted Nrf2 activation blocks diabetic cardiomyopathy via Akt-driven glycolysis and AMPK-PGC-1α fatty-acid oxidation.
    Ying Jiang, Dayun Tao, Zhiyu Jin, Zunyan Li, Xiuling He, Hao Zhou, Hang Zhu, Lina Ren.
      
    Keywords:  AMPK; Akt; Diabetic cardiomyopathy; Nrf2; PGC-1α
    DOI:  https://doi.org/10.1007/s00592-026-02660-1
  4. Front Mol Neurosci. 2026 ;19 1755292
    Lysosome trafficking across intracellular and intercellular networks in the brain.
    Dylan T Murphy, Chih Hung Lo.
      
    Keywords:  cell-cell interaction; intrinsically disordered proteins (IDPs); lysosome acidification; lysosome trafficking; microtubule transport; neurodegenerative diseases; neuron-glia communication; tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.3389/fnmol.2026.1755292
  5. Br J Pharmacol. 2026 Feb 20.
    Angiotensin-(1-9) attenuates diabetic cardiomyopathy by improving insulin resistance.
    Ignacio Norambuena-Soto, Pengfei Zhang, Yin Wang, Ling Fu, Danica Jimenez-Gallegos, Yunqiu Jiang, Vivian Yuan, Hongliang Li, Mario Chiong, Gerald Zapata-Torres, Yingfeng Deng, Marcelo J Kogan, Zhao V Wang, Sergio Lavandero.
       BACKGROUND AND PURPOSE: Diabetic cardiomyopathy is a clinical condition of ventricular dysfunction, with obesity and insulin resistance as the primary risk factors. Under this condition, the heart encounters lipotoxicity, which impairs cardiac insulin sensitivity and leads to cardiomyopathy. Angiotensin-(1-9) is a peptide of the counter-regulatory axis of the renin-angiotensin system with cardioprotective effects. However, its role in diabetic cardiomyopathy is unknown.
    EXPERIMENTAL APPROACH: To investigate the role of angiotensin-(1-9), we first induced lipotoxic stress in the heart by high-fat diet (HFD) feeding in mice. Angiotensin-(1-9) was then administered for 4 weeks using osmotic mini-pumps. Cardiac function was assessed, and insulin sensitivity was evaluated in heart tissues after insulin bolus injection. Moreover, lipotoxic stress in vitro was modelled by high glucose medium plus palmitate in neonatal rat ventricular myocytes (NRVMs).
    KEY RESULTS: Angiotensin-(1-9) improves myocardial function and reverts pathological cardiac remodelling under HFD feeding in mice. Moreover, angiotensin-(1-9) enhances whole-body glucose tolerance and reduces homeostatic model assessment of insulin resistance (HOMA-IR). We demonstrate that angiotensin-(1-9) increases insulin sensitivity in the heart and skeletal muscle but not in adipose tissue or the liver. Mechanistically, angiotensin-(1-9) does not affect insulin signalling in cardiomyocytes at baseline, whereas it significantly improves insulin action under lipotoxic stress through AT2 receptors and protein kinase A.
    CONCLUSION AND IMPLICATIONS: These findings demonstrate that angiotensin-(1-9) improves cardiac function under metabolic challenge and promotes insulin signalling in cardiomyocytes under lipotoxicity, which may shed light on the therapeutic exploration against diabetic cardiomyopathy.
    Keywords:  AT2 receptor; angiotensin‐(1–9); diabetic cardiomyopathy; insulin signalling
    DOI:  https://doi.org/10.1111/bph.70356
  6. Cell Chem Biol. 2026 Feb 18. pii: S2451-9456(26)00028-0. [Epub ahead of print]
    Lysosome-targeting chimeras enable targeted protein degradation.
    Bozhao Li, Yanyan Li, Jian Zhang, Siren Badama, Xian Zhao, Liping Wang, Tian Zhang, Xueting Wang, Xiaoqing Yi, Guo-Bin Ding, Xudong Wang, Guangjun Nie.
      Targeted protein degradation (TPD) has emerged as a powerful therapeutic paradigm by enabling the selective elimination of disease-associated proteins beyond the reach of conventional inhibition strategies. Among TPD approaches, lysosome-targeting chimeras (LYTACs) uniquely enable the degradation of extracellular and membrane-associated proteins through receptor-mediated endocytosis and lysosomal delivery. This Review provides a mechanistic and conceptual overview of LYTAC technology, emphasizing molecular classification based on ligand architecture, lysosome-targeting receptor engagement, and endocytic trafficking pathways. We discuss how receptors such as the cation-independent mannose-6-phosphate receptor and asialoglycoprotein receptor dictate internalization efficiency and degradation outcomes, and highlight key biochemical and cellular determinants governing target recognition, intracellular routing, and lysosomal processing. Finally, we examine major translational challenges, including tissue selectivity, pharmacokinetics, immunogenicity, and manufacturing constraints, and outline emerging design strategies such as ligand and linker engineering, modular scaffold optimization, and synthetic receptor recruitment that may enable next-generation LYTAC therapeutics with improved precision and clinical potential.
    Keywords:  LYTACs; extracellular protein degradation; lysosome-targeting chimeras; receptor-mediated endocytosis; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.008
  7. Front Pharmacol. 2026 ;17 1681783
    Repurposing metformin for cardioprotection: mechanisms and therapeutic potential across cardiovascular pathologies.
    Julia Khinchin, Ani Rakoubian, Valentina Romano, Thomas Ryan, Johnathan Yarbro, Satoru Kobayashi, Qiangrong Liang.
      Metformin, a cornerstone therapy for type 2 diabetes mellitus, has emerged as a promising cardioprotective agent with effects that extend well beyond glycemic control. This review synthesizes current evidence on the molecular and cellular mechanisms underlying metformin's glycemic control and cardiovascular benefits, highlighting both AMPK-dependent and AMPK-independent pathways. We examine its modulation of mitochondrial function, oxidative stress, inflammation, autophagy, and apoptosis across major cardiac conditions, including ischemia/reperfusion injury, heart failure, diabetic cardiomyopathy, and anthracycline-induced cardiotoxicity. By integrating evidence from both preclinical and clinical studies, we evaluate the translational potential of metformin's pleiotropic actions across specific cardiac pathologies and outline key directions for future research and therapeutic innovation. Together, these insights highlight metformin's promise in reshaping cardiovascular care beyond its traditional role in diabetes management.
    Keywords:  AMPK; anthracycline cardiotoxicity; autophagy; cardioprotection; diabetic cardiomyopathy; heart failure; ischemia-reperfusion injury; metformin
    DOI:  https://doi.org/10.3389/fphar.2026.1681783
  8. Nat Cell Biol. 2026 Feb 16.
    Adaptor-mediated recruitment of three dyneins to dynactin enhances force generation.
    Lu Rao, Xinglei Liu, Mirjam Arnold, Kyoko Okada, Richard J McKenney, Kristy Stengel, Simone Sidoli, Florian Berger, Arne Gennerich.
      Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2, which typically function with two dynein motors. We show that mechanical tension recruits a third dynein motor via an auxiliary BicD2 adaptor binding the light intermediate chain of the third dynein, stabilizing multidynein assemblies and enhancing force generation. Lis1 prevents dynein from transitioning into a force-limiting phi-like conformation, allowing single-dynein dynein-dynactin-BicD2 to sustain forces up to approximately 4.5 pN, whereas force generation often ends at about 2.5 pN without Lis1. Complexes with two or three dyneins generate 7 pN and 9 pN, respectively, consistent with a staggered motor arrangement that enhances collective output. Under load, dynein-dynactin-BicD2 primarily takes 8-nm steps, challenging existing dynein coordination models. These findings reveal adaptive mechanisms that enable robust intracellular transport under varying mechanical demands.
    DOI:  https://doi.org/10.1038/s41556-026-01877-0
  9. Am J Physiol Heart Circ Physiol. 2026 Feb 21.
    Type 2 Diabetes disrupts T-tubule and RyR2 organisation in male but not female rat ventricular muscle.
    Maryam Rahmani, Andrew J Taberner, Kenneth Tran, David J Crossman, June-Chiew Han.
      Females with diabetes often experience more severe cardiovascular outcomes than males with diabetes. It is unclear whether these sex-specific outcomes are rooted in distinct cellular alterations of key cardiac excitation-contraction coupling (ECC) proteins, specifically transverse tubules (T-tubules), ryanodine receptors (RyR2), and filamentous actin (F-actin). This study investigated myocardial ECC structures in both sexes under type 2 diabetic conditions and measured cardiac functional outcomes at muscle level. Type 2 diabetes was induced in male and female Wistar rats using a high-fat diet and low-dose streptozotocin protocol. Left ventricular trabeculae were isolated and subjected to mechano calorimetric experiments to quantify heat output and twitch force production. The same trabeculae were imaged using high-resolution Stimulated Emission Depletion (STED) microscopy to assess structural organisations of the T-tubule, RyR2, and F-actin. Diabetic rats of both sexes developed hyperglycaemia and glucose intolerance, without evidence of ventricular hypertrophy. Mechano energetic indices including activation heat, crossbridge economy, and twitch force kinetics were unaffected by diabetes in either sex. F-actin organisation was not affected by diabetes. However, compared with their respective controls, diabetic males, but not diabetic females, exhibited structural differences in cardiac ECC proteins: reduced T-tubule area and skeleton length, and enlarged RyR2 clusters and Calcium Release Units (CRU) with increased RyR2 density. These results show that structural reorganisation of cardiac RyR2 proteins occurred in diabetic males and not females, despite absence of ventricular hypertrophy and mechano-energetic dysfunction in the muscles of these two groups.
    Keywords:  F-actin; High-fat Diet; RyR2; Sex differences; T-tubule
    DOI:  https://doi.org/10.1152/ajpheart.00664.2025
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒23 at 12:47.