bims-lypmec 2025-07-13 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–07–13
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

Real-Time Monitoring of Adenosine Triphosphate Fluctuation in Lysosome during Autophagy/Mitophagy.
Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.
Clinical management of diabetic cardiomyopathy with insights into pathophysiology and diagnosis.
LIMP-2 deficiency-associated glycolipid abnormalities in mice.
Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism.
LRO biogenesis and function: what can we learn from mast cells?
The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.
Palmitic acid-induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration.
Role of Membrane Microdomains in Cardiac Protection: Strategies for Diabetic Cardiomyopathy.

ACS Appl Mater Interfaces. 2025 Jul 11.

Real-Time Monitoring of Adenosine Triphosphate Fluctuation in Lysosome during Autophagy/Mitophagy.

Jiwen Hu, Hong Wang, Xin Zhang, Chunfei Wang, Anna du Rietz, Mengtao Rong, Caroline Brommesson, Xiongyu Wu, Zhanxiao Wei, Ruilong Zhang, Xuanjun Zhang, Kajsa Uvdal, Zhangjun Hu.

  Autophagy, a lysosomal degradation pathway critical for cell survival, differentiation, development, and maintaining homeostasis, plays a crucial role in cellular health. Maintaining an adequate level of adenosine triphosphate (ATP), the central molecule in energy metabolism, is equally essential for these processes. However, the interplay between autophagy and energy metabolism remains incompletely understood due to technical challenges, including the need for high-precision, dynamic detection within organelles, and sensitivity to the acidic lysosomal environment. To address these limitations, we developed HR-MP, a ratiometric fluorogenic nanoprobe specifically designed for visualizing ATP levels in acidic lysosomes during autophagy. HR-MP exhibits selective, rapid, and quantitative ATP detection in vitro, allowing it to quantitatively monitor lysosomal ATP fluctuations in complex biological environments with excellent biocompatibility, membrane permeability, and lysosome-targeting ability. Importantly, HR-MP enables real-time tracking of ATP fluctuations during starvation- or drug-induced autophagy in living cells, providing a powerful tool for elucidating the links between autophagy and energy metabolism.

Keywords:  ATP monitoring; Förster resonance energy transfer (FRET); lysosome targeting; ratiometric fluorogenic nanoprobe; silica nanoparticles

DOI:  https://doi.org/10.1021/acsami.5c07496
Cardiovasc Diabetol. 2025 Jul 10. 24(1): 272

Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.

Yu Wei, Yang Ji, Jiahui Meng, Li Yu, Yongzhong Tang, Wei-Jin Fang.

   BACKGROUND: Impaired Ca2+ handling is involved in diabetic cardiomyopathy (DCM) progression. The activation of acid sphingomyelinase (ASMase) stimulated cardiomyocytes apoptosis and caused DCM. Here, we aimed to investigate whether ASMase regulates mitochondrial Ca2+ homeostasis by acting on mitochondrial calcium uptake 1 (MICU1) and mitochondria-associated endoplasmic reticulum membranes (MAMs) formation to induce apoptosis during DCM.
METHODS AND RESULTS: We established a type 2 diabetes model by combining high-fat diet (HFD) with streptozotocin (STZ) injection in wild-type and cardiomyocyte-specific ASMase deletion (ASMaseMyh6KO) mice. ASMase deletion restored HFD/STZ-induced cardiac dysfunction, remodeling, myocardial lipid accumulation and apoptosis. Single cell sequencing and Gene ontology (GO) enrichment analysis pointed to "cardiac muscle contraction" and "positive regulation of mitochondrial calcium ion concentration", which were confirmed by high glucose (HG, 30 mM) and palmitic acid (PA, 200 μM) induced mitochondrial Ca2+ overload in H9c2 cell lines at time dependence, accompanied by the upregulation of ASMase and MICU1 protein expressions. The similar effects were noted in ASMase overexpressed cardiomyocytes. Interestingly, endoplasmic reticulum (ER) Ca2+ level was decreased at the corresponding time, suggesting that increased mitochondrial Ca2+ level may be derived from ER. Notably, enhanced MAMs formation was found in HG + PA treated H9c2 cells, accompanied by blocked autophagy, similar results were obtained in ASMase overexpressing cells or HFD/STZ hearts. Loss of ASMase prevented HFD/STZ or HG + PA incubation induced cardiac hypertrophy, mitochondrialCa2+ overload, ROS production, autophagy blockage and MICU1 upregulation.
CONCLUSIONS: HFD/STZ-induced ASMase upregulation enhances MAMs formation, promoting mitochondrial Ca2+ overload through MICU1 activation, leading to ROS generation, autophagy blockage and apoptosis in DCM. Therefore, targeting ASMase-MICU1 pathway emerges as a potential therapeutic approach for managing DCM.

Keywords:  ASMase; Diabetic cardiomyopathy; MICU1; Mitochondrial calcium homeostasis

DOI:  https://doi.org/10.1186/s12933-025-02801-w
J Mol Cell Cardiol. 2025 Jul 05. pii: S0022-2828(25)00111-7. [Epub ahead of print]

Clinical management of diabetic cardiomyopathy with insights into pathophysiology and diagnosis.

David Chen, Andrew Sindone, Michael L H Huang, Karlheinz Peter, Alicia J Jenkins.

  Diabetes mellitus is associated with significant morbidity and premature mortality for which heart failure (HF) is a major cause. HF may be due to ischaemia, hypertension, uraemia, or a specific diabetic cardiomyopathy, and multiple causes may co-exist. A recent systematic review suggests that >40 % of people with type 2 diabetes have diastolic dysfunction without a reduction of cardiac systolic function. In people with type 1 diabetes without known cardiovascular disease, 16 % had systolic or diastolic dysfunction. Early diabetic cardiomyopathy is asymptomatic and can progress to symptomatic HF via increasing cardiomyocyte hypertrophy and death as well as cardiac fibrosis. The 5-year mortality rate for HF is similar or worse than many common cancers. There have been significant recent advances in HF treatment including sodium-glucose co-transport 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi), and promising therapies such as finerenone and glucagon-like peptide-1 receptor agonists (GLP-1RA). SGLT2i, finerenone, and GLP-1RA may also have a role in HF prevention in asymptomatic diabetic cardiomyopathy. While there is currently no specific treatment for diabetic cardiomyopathy that goes beyond general HF treatment, there is promising research into innovative technologies such as gene and stem cell therapies. Also, digital technologies will likely have an increasing role in diabetic cardiomyopathy treatment. Herein we review the pathophysiology, diagnosis, and treatment of diabetic cardiomyopathy, with a focus on existing, emerging, and potentially promising novel therapies. We provide practical tables that summarise treatments at each stage as well as important practice points for commonly prescribed drugs.

Keywords:  Cardiac metabolism; Cardioprotective therapies; Diabetes mellitus; Diabetic cardiomyopathy; Diagnostic approaches; Heart failure

DOI:  https://doi.org/10.1016/j.yjmcc.2025.06.013
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 08. pii: S1388-1981(25)00065-4. [Epub ahead of print] 159657

LIMP-2 deficiency-associated glycolipid abnormalities in mice.

Paulo Gaspar, André R A Marques, Maria J Ferraz, Markus Damme, Gertjan Kramer, Mina Mirzaian, Marion Gijbels, Roelof Ottenhoff, Cindy van Roomen, Herman S Overkleeft, Michael Schwake, Saskia Heybrock, Maria Carmo Macário, Paul Saftig, Johannes M Aerts.

  Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 -/- mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 -/- mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 -/- tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.

Keywords:  Cerebrosides; Cholesterol; GBA; Gaucher's disease; Glucocerebrosidase; Glucosylceramide; Glucosylcholesterol; LIMP-2; Lysosomes; Mass spectrometry; SCARB2

DOI:  https://doi.org/10.1016/j.bbalip.2025.159657
Nat Commun. 2025 Jul 08. 16(1): 6308

Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism.

Wing-Cheung Chan, Qian Zhao, Koon Ho Wong, Hok-Him Tang, Daniel Kam-Wah Mok, Lakhansing Pardeshi, Ye Chun Ruan, Yang Yang, Chi-Ming Wong, Clarence T T Wong, Yong-Juan Zhao, Ka Ying Chan, Zengsheng Yin, Howard Ho-Wai Leung, Xiyang Ma, Mary P Chau, Franco King-Chi Leung, Ying-Ying Lui, Shannon Wing-Ngor Au, Kailei Sun, Chin Yu Mok, Fang Wang, Cong Ma, Yu-Hin Ho, Xiang-Yang Ye, Man Lung Yeung, Yajing Zhang, Yan Xiang Zhao, Jiang Liu, Ka-Hing Wong, Larry M C Chow, Xiang David Li, Gary M Tse, Man-Kin Wong, Xiao Shen, Pauline Chiu, Ben C B Ko.

Tetrandrine (Tet) is a potent inhibitor of Ebola virus replication by blocking NAADP-dependent calcium release through endolysosomal two-pore channels (TPCs) and a moderately potent anti-tumor agent. Using a clickable photoaffinity probe, we identify lysosomal integral membrane protein-2 (LIMP-2) as a direct target of Tet and a key regulator of this calcium signaling. Tet binds LIMP-2's ectodomain, inhibiting lysosomal cholesterol and sphingosine transport, which alters lipid metabolism. Tet treatment and LIMP-2 depletion inhibit NAADP-dependent calcium release, reversible by removing lysosomal cholesterol and sphingosine. Sphingosine triggers lysosomal calcium release via TPCs and restores this signaling in Tet-treated or LIMP-2-deficient cells, revealing a LIMP-2-regulated, sphingosine-dependent lysosomal calcium pathway. At higher doses, Tet induces apoptosis through unfolded protein response activation independently of LIMP-2. These findings highlight Tet as a LIMP-2 inhibitor, elucidate its role in calcium signaling and cell death, and suggest therapeutic potential for Tet and LIMP-2 inhibitors in antiviral treatments.

DOI: https://doi.org/10.1038/s41467-025-61565-9
Front Cell Dev Biol. 2025 ;13 1613677

LRO biogenesis and function: what can we learn from mast cells?

Juan Eduardo Montero-Hernández, Kerui Zhang, Ulrich Blank, Gaël Ménasché.

  Lysosome-related organelles (LROs) are specialized compartments with cell type-specific roles. In mast cells (MCs), which are tissue-localized hematopoietic effector cells, LROs refer to secretory lysosomes also known as secretory granules (SGs) containing numerous pre-formed inflammatory mediators including proteases, proteoglycans, lysosomal enzymes, histamine and serotonin. Their release during MC activation is responsible for allergic, inflammatory manifestations, the fight against parasitic agents or the neutralization of toxins. Here, we provide an overview of knowledge describing the mechanisms underlying the biogenesis, secretion and biological functions of LROs in MCs. Decoding molecular mechanisms involved in LRO biogenesis and biology of MCs will benefit i) to other immune or non-immune cell types containing LROs and ii) can be exploited to design novel therapeutic approaches for the treatment of allergic and chronic inflammatory diseases caused by MC activation.

Keywords:  LRO fusion; LRO transport; lysosome-related organelle (LRO); mast cells; pre-formed inflammatory mediators; secretory granules

DOI:  https://doi.org/10.3389/fcell.2025.1613677
Elife. 2025 Jul 07. pii: RP101984. [Epub ahead of print]13

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.

Fan Zhang, Yuan Wang, Luyang Zhang, Chunjie Wang, Deping Chen, Haibo Liu, Ren Xu, Cole M Haynes, Jae-Hyuck Shim, Xianpeng Ge.

  The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

Keywords:  CHMP5; bone; cell biology; cell senescence; endolysosomal pathway; medicine; mouse; musculoskeletal disease; skeletal stem cell

DOI:  https://doi.org/10.7554/eLife.101984
Neural Regen Res. 2025 Jul 05.

Palmitic acid-induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration.

Eka Norfaishanty Saipuljumri, Jialiu Zeng, Chih Hung Lo.

  Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly associated with metabolic dysfunction, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. Central to this connection is the dysregulation of lipid metabolism, which extends beyond peripheral tissues to the brain, defective autolysosomal function, oxidative stress, inflammation, and insulin resistance. Lipids, which constitute over half of dry weight of the brain, play critical roles in energy provision, structural integrity, and synaptic function. Dysregulation of lipid metabolism contributes to neuroinflammation, impaired neuronal function, and disrupted blood-brain barrier integrity. Palmitic acid, a saturated fatty acid abundant in high-fat diets, serves as a key model for studying lipid-induced toxicity (lipotoxicity) in the brain. Palmitic acid disrupts autophagy and lysosomal function, mitochondrial function, triggering oxidative stress, contributing to neuroinflammation and neurodegeneration. These effects are particularly pronounced in neurons, which are highly susceptible to lipid-induced toxicity due to their high metabolic demands. Glial cells, including astrocytes, microglia, and oligodendrocytes, also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation, further contributing to neuroinflammation and demyelination. Therapeutic strategies, such as supplementation with polyunsaturated fatty acids, AMP-activated protein kinase activation, and lysosome-targeted interventions, show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis. This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Additionally, it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions. Advances in multi-omics technologies and a deeper understanding of intercellular crosstalk offer new avenues for developing targeted therapies to restore autolysosomal function, and attenuate neuroinflammation and neurodegeneration.

Keywords:  autolysosomal dysfunction; lipotoxicity; metabolic dysfunction; neuroinflammation; palmitic acid

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00432
Am J Physiol Heart Circ Physiol. 2025 Jul 10.

Role of Membrane Microdomains in Cardiac Protection: Strategies for Diabetic Cardiomyopathy.

Alice E Zemljic-Harpf, Jacqueline A Bonds, Juan Pablo Zuniga Hertz, Hemal H Patel.

  Diabetic cardiomyopathy (DCM) is a cardiac disorder characterized by structural and functional impairments independent of coronary artery disease. Membrane microdomains, including lipid rafts and caveolae, play a crucial role in cardiac signaling, insulin receptor trafficking, and ion channel regulation. In diabetes, disrupting these microdomains leads to impaired insulin signaling, oxidative stress, and mitochondrial dysfunction, exacerbating cardiac pathology. This review explores the role of caveolins and lipid rafts in DCM and how their dysfunction contributes to disease progression. We highlight how therapeutics used to manage diabetic patients may impact microdomain integrity. Future research should focus on targeting membrane microdomains for novel treatments.

Keywords:  Diabetic cardiomyopathy; caveolae; insulin signaling; lipid rafts; microdomains

DOI:  https://doi.org/10.1152/ajpheart.00139.2025