bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–08–23
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
  2. Tracking the Temporal Order of Mitochondrial and Lysosomal Damages with a Single Functional Probe: Lysosomal Damage Precedes Mitochondrial Damage under Hyperthermia.
  3. Neoliensinine promotes lysosomal cell death in T cell malignancies via a novel STING-TUBA1B pathway.
  4. ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.
  5. TMEM175 deficiency impairs autophagic degradation and alleviates mitochondrial oxidative damage in cardiomyocytes through AMPK activation.
  6. Surface-Engineered Carbon Dots for Monitoring of Lysosomal Viscosity and Organelle Dysfunction.
  1. iScience. 2026 Aug 21. 29(8): 116866
    Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
    Erin M Smith, Natali L Chanaday, Sandra Maday.
      Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by Galectin-3 recruitment to lumenal lysosomal β-galactosides, disrupted lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT (endosomal sorting complex required for transport) repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GTPase-activating protein (GAP), TBC1D15, was more robustly activated in astrocytes. By contrast, the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway, mediating lipid transfer between the endoplasmic reticulum (ER) and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.
    Keywords:  ESCRT; LLOMe; ORP9; PI4K2A; TBC1D15; astrocyte; lysosomal damage; neuron
    DOI:  https://doi.org/10.1016/j.isci.2026.116866
  2. Anal Chem. 2026 Aug 18. 98(32): 23762-23773
    Tracking the Temporal Order of Mitochondrial and Lysosomal Damages with a Single Functional Probe: Lysosomal Damage Precedes Mitochondrial Damage under Hyperthermia.
    Bin Zhan, Jiaqi Li, Jinxin Liu, Qingqing Lu, Minggang Tian.
      Mitochondrial or lysosomal damage is the initial step of apoptosis, and detecting their damaging sequences is crucial for understanding programmed cell death and related diseases. However, fluorescent probes capable of reporting their damaging order are rarely reported, owing to the deficiency of valid strategies. Herein, by rationally modifying targeting groups and employing a side-chain regulation strategy, a probe Trav was designed to detect the temporal order of lysosomal and mitochondrial damage. Trav targeted both mitochondria and lysosomes in living cells and distinguished them from each other with different fluorescence colors. Upon mitochondrial damage, Trav translocated to lysosomes, accompanied by a fluorescence color change. Subsequently, after lysosomal damage, Trav was relocated to the nucleus and emitted a third color. Similarly, if lysosomal damage occurs first, Trav migrates to mitochondria, which relocated into the nucleus after subsequent mitochondrial damage. Thus, Trav enabled reporting the damaging order of mitochondria and lysosomes through subcellular translocation and fluorescence color changes. Using Trav, we successfully revealed that in hyperthermia-induced injury lysosomal damage preceded mitochondrial damage, and this process was associated with increased levels of reactive oxygen species. Reducing agents, such as cysteine, can inhibit the injury. Trav holds promise as a valuable molecular tool for advancing research in related biomedical fields.
    DOI:  https://doi.org/10.1021/acs.analchem.6c03203
  3. Genes Dis. 2026 Nov;13(6): 101809
    Neoliensinine promotes lysosomal cell death in T cell malignancies via a novel STING-TUBA1B pathway.
    Po Hu, Yuxuan Huang, Zipeng Yu, Xiaolong Zhang, Guangming Yang, Yang Pan.
      The clinical treatment options for T cell malignancies (T-CMs) remain limited, and even the current popular immunotherapies have yet to demonstrate significant efficacy in addressing this disease. Identifying effective therapeutic targets for T-CMs and developing corresponding drugs are still critical goals in this field. Stimulator of interferon genes (STING) is highly expressed in T cells and plays a pivotal role in T cell immunity. However, the mechanisms underlying STING-mediated cell death are not well understood. Neoliensinine (NeoL), a unique bisbenzylisoquinoline alkaloid from Nelumbo nucifera Gaertn, has been shown to be promising as a cytotoxic agent in this context. Here, we investigated NeoL and uncovered a novel mechanism linking STING-induced lysosome-dependent cell death in T-CMs. NeoL was found to bind to and activate STING, promoting its trafficking to lysosomes for degradation. This process was coordinated by tubulin alpha 1b (TUBA1B), a key microtubule isoform. The trafficking of STING to lysosomes disrupted cholesterol homeostasis, leading to lysosomal cholesterol accumulation. This, in turn, triggered lysosomal dysfunction, including lysosomal damage, membrane permeabilization, and cell death. Blocking any part of the STING-TUBA1B-lysosomal cholesterol accumulation axis attenuated NeoL-induced lysosomal disorders and T-CM cell death without significant effect on normal peripheral blood mononuclear cells. NeoL also decreased the growth of T-CM-derived tumors in vivo. These findings suggest that targeting STING-TUBA1B in T-CMs with NeoL is a promising therapeutic approach and provide a potential agent for improving T-CM therapy.
    Keywords:  Cholesterol homeostasis; Lysosome-dependent cell death; Neoliensinine; Stimulator of interferon genes pathway; T cell malignancies
    DOI:  https://doi.org/10.1016/j.gendis.2025.101809
  4. Mol Cell. 2026 Aug 17. pii: S1097-2765(26)00513-7. [Epub ahead of print]
    ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.
    Natalia Jimenez-Moreno, Arianna Karageorgiou, Katie Winnington-Ingram, Jimi Wills, Chinmayi Pednekar, Melina Overhoff, Katherine Paine, Matthew Pearson, Lukas Gerasimavicius, Ann Wheeler, Natalia L Kononenko, Joseph A Marsh, Paul Verkade, Alex von Kriegsheim, Jon D Lane, Simon Wilkinson.
      Endoplasmic reticulum (ER)-phagy receptors have elusive physiological functions beyond ER remodeling. To gain insight into these, we screen for cytoplasmic interactors of well-known receptors in mouse pancreatic ductal adenocarcinoma cells. Our data subsequently reveal a non-canonical action of PRKAR1A, a subunit of protein kinase A (PKA), in binding and activating FAM134B/C. At a molecular level, an amphipathic helix in the otherwise-disordered C terminus of FAM134B directly binds PRKAR1A dimers. Multimodal imaging reveals that this interaction occurs at interorganellar contact sites between the ER and liquid-like condensates of PRKAR1A. Mechanistically, ER-condensate contacts promote clustering of FAM134B/C with LC3B and recruit lysosomes, forming degradation hubs. Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA. Underscoring the physiologic relevance of this, these cytoplasmic-facing actions of FAM134B/C result in RhoA-dependent cell morphologic and migratory control in response to cyclic AMP (cAMP) stimuli. Thus, interorganellar contacts expand the roles of FAM134B/C ER-phagy receptors beyond ER degradation.
    Keywords:  ER-phagy; LLPS; RHO GTPase; autophagy; cAMP; cancer; cell invasion; cytoskeleton; liquid-like condensate; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.027
  5. J Mol Cell Cardiol. 2026 Aug 18. pii: S0022-2828(26)00125-2. [Epub ahead of print]
    TMEM175 deficiency impairs autophagic degradation and alleviates mitochondrial oxidative damage in cardiomyocytes through AMPK activation.
    Qingliu Li, Nan Hu, Limei Zhao, Shaoxuan Zhang, Lulu Meng, Jinyu Zhou, Qiujie Li, Fucheng Lei, Xiaotong Yang, Meiqin Hu, Hua Zhu, Pengzhou Hang, Jing Zhao.
      Transmembrane protein 175 (TMEM175) is a lysosomal proton-activated and proton-selective channel critical for regulating lysosomal membrane potential and acidity. However, its role in cardiomyocyte physiological and stress response remains unclear. Here, we investigated the function of TMEM175 in mitochondrial homeostasis using H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVMs) under physiological conditions and during hydrogen peroxide (H2O2)-induced oxidative stress. Under physiological conditions, genetic knockout of TMEM175 impaired mitochondrial respiration, reduced mitochondrial superoxide, and attenuated autophagic clearance. In contrast, under H2O2-induced stress, TMEM175 deletion significantly alleviated mitochondrial dysfunction and cell death, despite autophagic flux being primarily stalled at the degradation stage. Mechanistically, TMEM175 deficiency activated AMP-activated protein kinase (AMPK), and silencing AMPK reversed the cytoprotective effects of TMEM175 deletion against H2O2 injury. Pharmacological inhibition of TMEM175 with 2-phenylpyridin-4-ylamine (2-PPA) in H9c2 and NRVMs recapitulated key phenotypes observed in genetic knockout models. Furthermore, 2-PPA improved cardiac function and attenuated histopathological injury in myocardial infarction mice. Together, these findings reveal a dual role for TMEM175: it maintains lysosomal-mitochondrial communication under basal conditions, yet its inhibition protects against oxidative stress primarily through AMPK activation. This study identifies TMEM175 as a novel lysosomal regulator of cardiac mitochondrial resilience and highlights its potential role in the cellular response to oxidative injury in cardiomyocytes.
    Keywords:  AMP-activated protein kinase; Cardiomyocyte; Hydrogen peroxide; Lysosome; Mitochondria; Transmembrane protein 175
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.007
  6. Small. 2026 Aug 16. e75280
    Surface-Engineered Carbon Dots for Monitoring of Lysosomal Viscosity and Organelle Dysfunction.
    Upasana Mohapatro, Prakash Kumar Senapati, Sujit K Bhutia, Sasmita Mohapatra.
      The development of robust, photostable nanoprobes for precise organelle targeting remains a cornerstone in chemosensing and advanced bioimaging. Alterations in the lysosomal microenvironment serve as an indicator of organelle health and disease progression. Herein, a sustainable synthetic strategy is presented for benzothiazole-modified carbon dots (LysoDots), engineered for specific lysosome localization and viscosity monitoring. LysoDots display a viscosity-dependent fluorescence enhancement in glycerol-water systems while remaining insensitive to physiological pH and temperature variations. This turn-on response allows for the high-fidelity tracking of lysosomal microviscosity changes induced by exogenous stimuli, such as nystatin, and endogenous processes like rapamycin-induced autophagy. Confocal imaging demonstrates a remarkable colocalization of LysoDots with the commercial lysosome marker, LysoTracker Green (LTG), showing a Pearson's correlation coefficient of 0.92 in CAL-33 oral carcinoma cells, with the red emission effectively differentiating lysosomal viscosity profiles between cancerous and non-cancerous cells. Furthermore, the LysoDots were successfully employed in a neuronal model, SH-SY5Y cells, where the probe effectively tracked glutamate-induced lysosomal dysfunction, mimicking the pathology of lysosomal storage disorders, along with the viscosity restoration mediated by trehalose. These findings highlight the potential of LysoDots as a biocompatible, photostable, multi-functional nanomaterial for long-term monitoring of lysosomal dynamics and cellular homeostasis.
    Keywords:  autophagy monitoring; carbon dots; lysosomal microviscosity; organelle dysfunction; organelle targeting; sustainable nanomaterials
    DOI:  https://doi.org/10.1002/smll.75280
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