bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–02–15
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
  2. Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.
  3. Spatiotemporal regulation of endocytic membrane trafficking by voltage-sensing phosphatase (VSP) in zebrafish enterocytes.
  4. Targeting Perilipin 5 Ameliorates Diabetic Cardiomyopathy via Regulating Glycolysis and Mitochondrial Dynamics.
  5. AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
  6. A sensitive pH fluorescent probe with large Stokes shift and narrow transition for lysosome imaging during cell cycle.
  1. Arch Toxicol. 2026 Feb 07.
    Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
    Shunichi Hatamiya, Masatsugu Miyara, Nanako Takahashi, Ami Oguro, Yaichiro Kotake.
      Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A1, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700 nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A1 in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.
    Keywords:  CASM; LC3; Lysosome; Noncanonical autophagy; TFEB; Tributyltin
    DOI:  https://doi.org/10.1007/s00204-026-04300-7
  2. J Am Chem Soc. 2026 Feb 10.
    Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.
    An Yan, Yuhan Kong, Yuxing Shang, Yifan Ge, Hang Xing, Di Li.
      Visualization of lysosomes in living cells is essential for understanding their physiological functions; yet, most probes that target the lysosomal interior often disrupt luminal chemistry, exhibit signal leakage, and fail to support long-term imaging. To address these challenges, we developed RELAY (Relocation of Endocytic Leaflet tAg to modifY organelles), a topology-preserving labeling strategy to transfer the inner-leaflet tags on the plasma membrane to the cytosol-facing outer leaflet of lysosomes. RELAY employs liposome-cell membrane fusion to anchor fluorescent DNA probes with phosphorothioate (PS) backbones on the cytoplasmic inner leaflet of the plasma membrane, followed by endocytic trafficking that preserves the membrane topology and relocates the probes onto the lysosomal outer surface. Because this labeling occurs on the lysosomal exterior that is protected from luminal degradation and the PS backbone resists nuclease degradation, RELAY enables highly stable asymmetric labeling that sustains week-long lysosome imaging in living cells. Using this approach, we visualized lysosomal dynamics during cellular senescence and discovered random, unidirectional, intercellular lysosomal transfer in cell-cell communications via tunnelling nanotubes. Holding the capability for prolonged, high-fidelity visualization of lysosomes, RELAY facilitates the exploration of their biological functions.
    DOI:  https://doi.org/10.1021/jacs.5c21974
  3. Biochim Biophys Acta Gen Subj. 2026 Feb 09. pii: S0304-4165(26)00016-4. [Epub ahead of print] 130916
    Spatiotemporal regulation of endocytic membrane trafficking by voltage-sensing phosphatase (VSP) in zebrafish enterocytes.
    Adisorn Ratanayotha, Natsuki Mizutani, Fumiko Takenaga, Takafumi Kawai, Yasushi Okamura.
      In developing vertebrates, nutrient uptake by specialized epithelial cells is primarily mediated by endocytosis, a process driven by dynamic phosphoinositide remodeling that regulates vesicle formation and endosomal maturation. Voltage-sensing phosphatase (VSP), a unique membrane protein that couples changes in membrane potential to phosphoinositide hydrolysis, is expressed in zebrafish lysosome-rich enterocytes (LREs), which mediate endocytosis-dependent nutrient absorption during development. However, the molecular mechanisms by which zebrafish VSP (Dr-VSP) regulates endocytic membrane trafficking remain unclear. Here, we elucidate by confocal imaging that Dr-VSP localizes to subapical endomembranes and dynamically redistributes to the apical plasma membrane during nutrient uptake, where it promotes early vesicle formation and maintains proper endolysosomal organization. Loss of Dr-VSP reduces early endocytic vesicles and disrupts downstream recycling and lysosomal compartments, leading to defective nutrient absorption. Electrophysiological analyses showed that extracellular or luminal acidic pH suppresses Dr-VSP voltage sensing, consistent with its activity being confined to the apical plasma membrane where voltage, pH, and phosphoinositide conditions are favorable for activation. These findings indicate that Dr-VSP acts as a voltage- and pH-regulated phosphoinositide phosphatase during the early phase of endocytosis at the plasma membrane, preceding lysosomal digestion. This work defines a functional role for VSPs in epithelial nutrient uptake in vertebrate enterocytes and points to a novel electrochemical mechanism underlying membrane trafficking in vertebrates.
    Keywords:  Endocytosis; Epithelial physiology; Lysosome-rich enterocyte; Membrane trafficking; Phosphoinositide; Voltage-sensing phosphatase; Zebrafish
    DOI:  https://doi.org/10.1016/j.bbagen.2026.130916
  4. Clin Sci (Lond). 2026 Feb 09. pii: CS20256032. [Epub ahead of print]
    Targeting Perilipin 5 Ameliorates Diabetic Cardiomyopathy via Regulating Glycolysis and Mitochondrial Dynamics.
    Qing Zhou, Kai Guo.
      This study investigates how Perilipin 5 (Plin5), a lipid droplet-associated protein crucial for regulating intracellular lipid metabolism, modulates glycolysis, apoptosis, and mitochondrial function under high glucose conditions, with a focus on its therapeutic potential in Diabetic cardiomyopathy (DCM). AC16 human cardiomyocyte cells and human cardiac fibroblasts (HCFs) were transfected with Plin5-overexpressing lentivirus. An in vivo DCM model was established in wild-type and Plin5-knockout mice using a high-fat diet (HFD) combined with streptozotocin (STZ) injection. Cardiac function was evaluated, and cellular mechanisms were assessed using molecular biology techniques and single-cell RNA sequencing analysis. Plin5 overexpression significantly enhanced glycolysis (e.g., a 2.5-fold increase in extracellular acidification rate, p<0.001) in both AC16 and HCFs. In AC16 cells, high glucose treatment upregulated Plin5 expression, whereas in HCFs, it led to downregulation. Apoptosis-related protein levels, including BCL-2 and cleaved Caspase-3, were modulated by Plin5 overexpression, with a notable impact under high glucose conditions. Cardiac ultrasound revealed significant differences in systolic function (EF values) across experimental groups. Ki67 staining showed enhanced cardiomyocyte proliferation in Plin5-overexpressing groups under normal glucose conditions, while TUNEL assays indicated reduced apoptosis, though this effect was attenuated under high glucose conditions. Bioinformatics analysis revealed a significant upregulation of fatty acid metabolism pathways in the diabetic heart, with Plin5 expression specifically increased in cardiomyocytes. In summary, this study demonstrates that Plin5 plays a critical role in regulating glycolysis, apoptosis, and cardiomyocyte proliferation, particularly under varying glucose conditions, identifying it as a potential therapeutic target for DCM.
    Keywords:  Apoptosis; Cardiac metabolism; Diabetic cardiomyopathy; Exercise; Glycolysis; Metabolic Reprogramming; Metabolic regulation; Mitochondrial dysfunction; Mitochondrial function; Perilipin 5
    DOI:  https://doi.org/10.1042/CS20256032
  5. Autophagy. 2026 Feb 09.
    AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
    Florentina Negoita, Conchita Fraguas Bringas, Kristina Hellberg, Katarzyna M Luda, Hongling Liu, Zhiyuan Li, Joyceline Cuenco, Jin-Feng Zhao, Gajanan Sathe, Ian G Ganley, Gopal P Sapkota, Kei Sakamoto.
      TFEB (transcription factor EB) is a critical regulator of lysosomal biogenesis, macroautophagy/autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were reported to be essential for transcriptional activation of TFEB. In sharp contrast to this proposition, we demonstrate that AMPK activation leads to the dephosphorylation of the C-terminal sites. We show that a synthetic peptide encompassing the C-terminal serine residues of TFEB is a poor substrate of AMPK in vitro. Treatment of cells with an AMPK activator (MK-8722), glucose deprivation or MTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at the MTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722- but not torin1-induced dephosphorylation and induction of the TFEB target genes.
    Keywords:  BAY-3827; MK-8722; MTOR; TFE3; coordinated lysosomal expression and regulation; reversible phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2026.2629720
  6. Talanta. 2026 Feb 10. pii: S0039-9140(26)00189-X. [Epub ahead of print]304 129534
    A sensitive pH fluorescent probe with large Stokes shift and narrow transition for lysosome imaging during cell cycle.
    Bochao Chen, Jixiang Zhang, Yifan Zhong, Xi Liu, Ji Xu, Ningning Cui, Jin Zhou.
      Intracellular pH plays a crucial role in regulating cellular functions, and its subtle changes can influence normal physiological activities and contribute to various diseases. Although numerous probes have been developed for detecting microenvironmental pH in living cells, their broad dynamic ranges induce blurred imaging boundaries and may generate false-positive results, compromising the accurate detection of subtle pH fluctuations. In response to these issues, we designed and synthesized a novel 1,8-naphthalic anhydride-based pH fluorescent probe (NAM) that demonstrated highly sensitive responses to pH changes with a narrow transition range spanning just 2.4 pH units. The pH responsiveness of NAM originated from the deprotonation of its aniline group, which induced an enhanced intramolecular charge transfer (ICT) process. This mechanism enables NAM to exhibit a remarkable 15-fold fluorescence enhancement at 569 nm with a pKa value of 6.71 and a significant Stokes shift of 112 nm. Furthermore, NAM specifically targets lysosomes and was successfully employed to detect intracellular pH fluctuations induced by lipopolysaccharide (LPS), nutrient deprivation and chloroquine treatment. Significantly, we demonstrate for the first time that NAM achieved pH imaging analysis across different cell cycle phases. During the transition from G0/G1 to S phase, intracellular pH gradually alkalinizes, followed by rapid acidification in the G2/M phase. These observations reflected the dynamic balance between energy storage and consumption during cell cycle progression. These distinctive features position NAM as a promising tool for investigating physiological and pathological processes associated with abnormal pH variations.
    Keywords:  Cell cycle; Fluorescent probe; Narrow transition; pH
    DOI:  https://doi.org/10.1016/j.talanta.2026.129534
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