bims-lypmec 2026-09-27 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–09–27
seven papers selected by
Satoru Kobayashi, New York Institute of Technology

Subclinical Diabetic Cardiomyopathy: Detectable but Not Yet Actionable.
Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.
Lysosomal membrane localization of organic anion transporting polypeptide 2B1 in human hepatocytes.
Dynamic imbalance of mitochondria-associated ER membranes in cardiovascular disease: mechanisms, context dependence and therapeutic potential.
Asb2-KIF11 Axis Protects Against Heart Failure by Restoring Lysosomal Distribution and Mitochondrial Homeostasis.
mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.

J Am Heart Assoc. 2026 Sep 24. e053346

Subclinical Diabetic Cardiomyopathy: Detectable but Not Yet Actionable.

Avnish Tripathi.



Keywords:  Editorials; cardiac magnetic resonance imaging; diabetes; heart failure; myocardial strain; ventricular remodeling

DOI:  https://doi.org/10.1161/JAHA.126.053346
J Cell Physiol. 2026 Sep;241(9): e70231

Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.

Debasmita Bhattacharya, Neushaw Moradi, David A Hood.

  Lysosomes are important organelles for the degradation of unwanted biomolecules via autophagy. Lysosomal dysfunction is apparent in ageing tissues, and can cause various neurodegenerative diseases. It is imperative to understand the mechanisms and implications of lysosomal malfunction and to find strategies to ameliorate diseases. To investigate this, we induced lysosomal dysfunction with Bafilomycin A1 (BAF), a drug that hinders lysosomal acidification by blocking vATPase-mediated proton pumping, in myoblasts and myotubes. Myotubes were subjected to chronic contractile activity (CCA) to mimic "exercise" to evaluate any therapeutic potential and reversal of pathophysiology. Induced lysosomal dysfunction was evident from impaired processing of the protease cathepsin B, enhanced lysosomal accumulation and increased autophagic markers Lamp1, p62, and the LC3II/I ratio. BAF attenuated lysosomal protease degradation measured using the substrate DQ-BSA in both myoblasts and myotubes. Many of the adverse effects generated by BAF in myotubes were reversed by CCA, manifested by a decrease in immature cathepsin B, a down-regulation of Lamp1, p62, LC3II/I and partial restoration of lysosomal protein degradation enzymatic capacity. To investigate further improvements in lysosomal function in a healthy cellular model, we treated myotubes with C1, a curcumin analogue. C1 decreased Lamp1, p62 and the LC3II/I ratio, all of which indicate improved lysosomal function and autophagosome clearance with a greater lysosomal ability to degrade substrates. Additionally, C1 was able to mimic the improved mitochondrial content induced by CCA. Thus, contractile activity and curcumin analogues may provide useful therapeutic potential to resuscitate lysosomal function, improve muscle health and ameliorate lysosome-mediated diseases. NEW AND NOTEWORTHY: This study explores the potential of chronic contractile activity (CCA) in reversing the compromised lysosomes caused by the disruption of lysosomal acidification in myotubes. Remarkably, CCA mitigated the effects of Bafilomycin A1-induced lysosomal dysfunction, enhancing protease activity and increased mitochondrial content. Treatment of myotubes with the curcumin analogue C1 reduced lysosomal accumulation and enhanced mitochondrial content suggesting that contractile activity-based interventions and small-molecule modulators of lysosomal pathways may represent promising complementary strategies for treating lysosome-related diseases and enhancing muscle health.

Keywords:  autophagy; bafilomycin A; exercise; lysosomes; mitochondria

DOI:  https://doi.org/10.1002/jcp.70231
Drug Metab Dispos. 2026 Aug 11. pii: S0090-9556(26)00655-0. [Epub ahead of print]54(10): 100386

Lysosomal membrane localization of organic anion transporting polypeptide 2B1 in human hepatocytes.

Yeseul Ahn, Jacqueline B Tiley, Bhagwat Prasad, Kim L R Brouwer.

  Organic anion transporting polypeptide 2B1 (OATP2B1) is a basolateral plasma membrane uptake transporter expressed in hepatocytes. However, the cellular internalization and degradation pathways of OATP2B1 remain poorly characterized. Filling this knowledge gap is critical for improving predictions of OATP2B1 substrate disposition and OATP2B1-mediated drug interactions. This study investigated the localization and primary degradation pathway of OATP2B1 in human hepatocytes and examined whether OATP2B1 localization was affected by metabolic dysfunction-associated steatohepatitis in human liver tissue. Sandwich-cultured human hepatocytes (SCHHs) were treated with either 25 μM chloroquine (CQ) or 10 μM MG-132 to inhibit lysosomal or proteasomal degradation, respectively. Following treatment, SCHHs were fixed and stained for OATP2B1 and lysosome-associated membrane protein (LAMP) 1, followed by confocal imaging and subsequent object-based quantitative analysis. Lysosomal inhibition by CQ in SCHHs resulted in significant accumulation of intracellular OATP2B1, which displayed major colocalization with the lysosomal marker, LAMP1 (20% ± 9.38% vs 9.5% ± 5.25%; CQ vs control, respectively; P < .0001). In contrast, the OATP2B1 total object volume and intracellular localization remained unchanged after MG-132 treatment. OATP2B1 colocalization with LAMP1 was significantly higher in liver tissue from patients with metabolic dysfunction-associated steatohepatitis (10.47% ± 4.95%) compared with control liver tissue (6.00% ± 2.06%; P < .0001). Super-resolution imaging using stimulated emission depletion microscopy revealed that OATP2B1 was localized on lysosomal membranes. In conclusion, these findings demonstrate that OATP2B1 degrades primarily via lysosomes in human hepatocytes. Lysosomal dysfunction associated with some xenobiotics or disease may increase OATP2B1 localization on lysosomal membranes. SIGNIFICANCE STATEMENT: This study confirms that lysosomes are the predominant degradation pathway for the basolateral membrane protein organic anion transporting polypeptide 2B1 (OATP2B1) in human hepatocytes. Super-resolution imaging revealed that OATP2B1 is localized on lysosomal membranes. Both lysosomal inhibition by chloroquine in vitro and lysosomal dysfunction associated with metabolic dysfunction-associated steatohepatitis in human liver tissue increased OATP2B1 colocalization with the lysosomal membrane marker.

Keywords:  Hepatic transporter; Lysosomes; Metabolic dysfunction–associated steatohepatitis; OATP2B1; Stimulated emission depletion microscopy

DOI:  https://doi.org/10.1016/j.dmd.2026.100386
Front Cell Dev Biol. 2026 ;14 1931748

Dynamic imbalance of mitochondria-associated ER membranes in cardiovascular disease: mechanisms, context dependence and therapeutic potential.

Yuhong Tang, Dezhao Liu, Beibei Luo, Feng Huang.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites that coordinate structural and functional communication between the endoplasmic reticulum (ER) and mitochondria. By organizing tethering complexes, calcium channels, lipid-transfer machinery, and stress-responsive signaling modules, MAMs regulate Ca2+ homeostasis, lipid metabolism, mitochondrial dynamics, mitophagy, oxidative stress, endoplasmic reticulum stress, and cell fate determination. Increasing evidence indicates that MAMs dysfunction is critically involved in the initiation and progression of cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, myocardial infarction, diabetic cardiomyopathy, dilated cardiomyopathy, and heart failure. In these settings, disrupted or excessive ER-mitochondria coupling can trigger mitochondrial Ca2+ overload, metabolic remodeling, reactive oxygen species accumulation, inflammatory activation, and programmed cell death. Conversely, preserved or appropriately remodeled MAMs integrity supports mitochondrial bioenergetics, adaptive stress responses, and cardiomyocyte or vascular cell survival. This review summarizes the molecular architecture and biological functions of major MAMs-associated complexes, and discusses their context-dependent roles in cardiovascular pathophysiology. We further highlight the therapeutic potential of targeting MAMs structure and function as a strategy to restore organelle homeostasis and improve cardiovascular outcomes.

Keywords:  calcium homeostasis; cardiovascular disease; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fcell.2026.1931748
Circulation. 2026 Sep 22.

Asb2-KIF11 Axis Protects Against Heart Failure by Restoring Lysosomal Distribution and Mitochondrial Homeostasis.

Yicheng Lv, Zhao Sha, Shi Peng, Zhenzhen Duan, Qingye Zeng, Shengli Li, Hao Wu, Xiaoyu Zhang, Xiaoxun Huang, Jincheng Zhang, Shengkai Zuo, Deping Kong.

   BACKGROUND: Heart failure remains a leading cause of mortality globally, driven by persistent mitochondrial dysfunction and maladaptive cardiac hypertrophy. Although impaired autophagic flux contributes to cardiac deterioration, the precise molecular mechanisms are still unclear. The ubiquitin-proteasome system serves as a critical regulator linking protein ubiquitination to autophagic flux and mitochondrial homeostasis. Asb2 (ankyrin repeat-containing protein with suppressor of cytokine signaling box 2), a muscle-specific E3 ubiquitin ligase essential for embryonic cardiogenesis, is uncharacterized in adult cardiac homeostasis and disease pathogenesis.
METHODS: Male mice with inducible cardiomyocyte-specific Asb2 knockout were generated to investigate Asb2's role in cardiac remodeling. Adeno-associated virus 9-mediated cardiomyocyte-specific Asb2 overexpression and KIF11 (kinesin family member 11) downregulation were used in transverse aortic constriction-induced hypertrophy and aging models. RNA sequencing, metabolite profiling, and mass spectrometry were used to assess the molecular mechanism by which Asb2 regulates cardiac metabolism and hypertrophy.
RESULTS: Asb2β expression was significantly reduced in multiple forms of human cardiomyopathy and in hypertrophic murine hearts. Inducible Asb2 deletion in adult male mice led to the spontaneous development of cardiac hypertrophy and heart failure, accompanied by progressive accumulation of dysfunctional mitochondria and metabolic dysregulation. Mechanistically, Asb2 deficiency impaired ubiquitin-mediated degradation of KIF11, causing aberrant peripheral lysosomal redistribution and disrupting autophagosome-lysosome fusion, which resulted in impaired late-stage autophagic flux and metabolic disturbances. Notably, therapeutic restoration of Asb2 expression via adeno-associated virus 9-mediated delivery attenuated pressure overload-induced and age-related cardiac hypertrophy and heart failure. Moreover, both genetic and pharmacological inhibition of KIF11 effectively restored autophagic flux and mitochondrial homeostasis, thereby reversing pathological cardiac remodeling in Asb2-deficient hearts and transverse aortic constriction-induced cardiac dysfunction.
CONCLUSIONS: Asb2 is a novel regulator of mitochondrial quality control in cardiomyocytes via KIF11-mediated lysosomal redistribution. Targeting the Asb2-KIF11 axis may be a promising strategy for improving mitochondrial homeostasis and cardiomyocyte function in chronic heart failure.

Keywords:  Asb2; KIF11; autophagic flux; heart failure; lysosomal positioning; mitochondrial quality control

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080625
Sci Adv. 2026 Sep 25. 12(39): eaee1905

mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.

Alex Zaufel, Wenfei Sun, Nunzia Pastore, Ulrike Taschler, Carina Wagner, Hubert Hackl, Judith Sommer, Dagmar Silbert-Wagner, Jan G Hengstler, Brigitte Begher-Tibbe, Rudolf Stauber, Dagmar Kolb, Martin Troetzmueller, Benjamin Gottschalk, Chelsea Thorsheim, Eva-Lena Stange, Mathias W Hornef, Olga Pivovarova-Ramich, Andreas F H Pfeiffer, Kylie P Matchett, Anne Loft, Stephan Herzig, Neil C Henderson, Andrea Ballabio, Zoltan Arany, Christian Wolfrum, Peter Fickert, Tarek Moustafa.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non-12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

DOI: https://doi.org/10.1126/sciadv.aee1905
Circulation. 2026 Sep 22.

Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.

Yufeng Hu, Wei Li, Manli Hu, Song Tian, Siyi Zhou, Jiayi Liu, Xu Cheng, Changjiang Zhang, Yingjie Zuo, Jiaxing Zhang, Dianyu Liu, Yang Hu, Yuanbao Chen, Xin Li, Lei Luo, Hailong Yang, Lan Bai, Hui Liu, Péter Ferdinandy, Mario Chiong, Mayarling Francisca Troncoso, Jinying Wen, Jingjing Cai, Xiao-Jing Zhang, Zhi-Gang She, Xin Zhang, Hongliang Li.

   BACKGROUND: Excessive unnecessary protein accumulation in cardiomyocyte is a leading contributor for pathological cardiac hypertrophy and has been found closely regulated by the mTORC1 (mechanistic target of rapamycin complex 1) signaling and lysosome transmembrane proteins. However, the precise regulatory mechanism stratifying mTORC1 signaling and the specific functions of lysosomal proteins in protein homeostasis of cardiomyocytes remain largely unidentified.
METHODS: We screened lysosomal genes conserved in mice, rats, and humans. Adenoviral infection of rat cardiomyocytes was used to assess the functional role of LAPTM4A (lysosome-associated protein transmembrane 4A). To evaluate its effects in vivo, adeno-associated virus 9 driven by the cardiac troponin T promoter was used for cardiomyocyte-specific expression. RNA sequencing and mass spectrometry-based proteomics were performed to elucidate the underlying molecular mechanisms. Last, a dual-luciferase reporter assay was used to screen a Food and Drug Administration-approved drug library for compounds that suppress LAPTM4A expression.
RESULTS: Lysosomal transmembrane proteins expressed in cardiomyocytes were screened for their roles in regulating hypertrophy, and LAPTM4A emerged as a potent promoter of cardiomyocyte hypertrophy and prohypertrophic gene expression. Overexpression of LAPTM4A aggravated cardiac remodeling and dysfunction by enhancing mTORC1-p70S6K (70-kDa ribosomal protein S6 kinase)/4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1)-mediated protein synthesis, without affecting lysosomal autophagy, in a NEDD4L (neural precursor cell expressed developmentally downregulated 4-like)-dependent manner. Mechanistically, LAPTM4A directly interacted with NEDD4L, facilitating K63-linked ubiquitination of AKT (protein kinase B [v-akt murine thymoma viral oncogene homolog]) and subsequent activation of mTORC1 signaling. Cardiomyocyte-specific deletion of LAPTM4A significantly attenuated myocardial hypertrophy and fibrosis induced by transverse aortic constriction in mice. Furthermore, a dual-luciferase reporter screen identified magnolol, a Food and Drug Administration-approved compound, as a suppressor of LAPTM4A expression with marked cardioprotective effects in vivo.
CONCLUSIONS: Our study identified a novel mTORC1 booster LAPTM4A and verified interrupting the LAPTM4A-mTORC1 axis can significantly inhibit excessive protein synthesis and pathological cardiac hypertrophy, which might represent an attractive therapeutic approach for this disease.

Keywords:  LAPTM4A; abnormal protein accumulation; cardiac hypertrophy; mTORC1

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080371