bims-lypmec 2025-07-27 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–07–27
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.
Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.
Ceramide and the membrane-fusion activity of LC3/GABARAP autophagy proteins.
TRPML3‑mediated lysosomal Ca2+ release enhances drug sequestration and biogenesis, promoting osimertinib resistance in non‑small cell lung cancer.
The Mechanical Role of YAP/TAZ in the Development of Diabetic Cardiomyopathy.
Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca2+ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.
PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.
Cardiac digital twins: a tool to investigate the function and treatment of the diabetic heart.

J Biol Chem. 2025 Jul 17. pii: S0021-9258(25)02324-5. [Epub ahead of print] 110474

Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.

Taiki Sawai, Yoshitsugu Nakamura, Shigeki Arawaka.

  Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown of a modulator for autophagosome formation, ATG5, BECN1 or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein, which is an aggregate-prone protein responsible for neuronal loss in Parkinson's disease. The blockade of autophagic secretion by knockdown of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these knockdowns induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 knockdown caused accumulation of Triton X-100-insoluble α-synuclein against induction of lysophagy. GBA knockdown showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, knockdown blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4 or RAB8A knockdown further accelerated accumulation of Triton X-100-insoluble α-synuclein caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4 or RAB8A knockdown blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these knockdowns impair α-synuclein proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.

Keywords:  Parkinson disease; autophagy; lysosome; protein secretion; proteostasis; synuclein

DOI:  https://doi.org/10.1016/j.jbc.2025.110474
Nat Commun. 2025 Jul 19. 16(1): 6668

Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.

Xue Han, Ruyi Zheng, Jiajia Zhang, Yanan Liu, Ze Li, Guoxuan Liu, Jianing Zheng, Weiqi Li, Zijun Liang, Mengyang Wang, Jie Yu, Qiaojuan Shi, Huazhong Ying, Guang Liang.

Deubiquitinating modification of proteins is involved in the pathogenesis of diseases. Here, we investigated the role and regulating mechanism of a deubiquitinating enzyme (DUB), ovarian tumor domain-containing protein 1 (OTUD1), in diabetic cardiomyopathy (DCM). We find a significantly increased OTUD1 expression in diabetic mouse hearts, and single-cell RNA sequencing shows OTUD1 mainly distributing in cardiomyocytes. Cardiomyocyte-specific OTUD1 knockout prevents cardiac hypertrophy and dysfunction in both type 2 and type 1 diabetic male mice. OTUD1 deficiency restores cardiac AMPK activity and mitochondrial function in diabetic hearts and cardiomyocytes. Mechanistically, OTUD1 binds to AMPKα2 subunit, deubiquitinates AMPKα2 at K60/K379 sites, and then inhibits AMPKT172 phosphorylation through impeding the interaction of AMPKα2 and its upstream kinase CAMKK2. Finally, silencing AMPKα2 in cardiomyocytes abolishes the cardioprotective effects of OTUD1 deficiency in diabetic mice. In conclusion, this work identifies a direct regulatory DUB of AMPK and presents a OTUD1-AMPK axis in cardiomyocytes for driving DCM.

DOI: https://doi.org/10.1038/s41467-025-61901-z
Cell Mol Life Sci. 2025 Jul 19. 82(1): 283

Ceramide and the membrane-fusion activity of LC3/GABARAP autophagy proteins.

Yaiza R Varela, Camila C Aguirre, Marina N Iriondo, Uxue Ballesteros, M Isabel Collado, Asier Etxaniz, L Ruth Montes, Felix M Goñi, Alicia Alonso.

  Macroautophagy is a cellular degradation process characterized by the formation of the double-membrane structure termed autophagosome (AP). The process of AP formation is not fully understood, but it is thought to happen through the combined action of direct lipid transfer and incorporation of new vesicles to the edges of the growing structure. Human LC3/GABARAP autophagy-related proteins are known to induce vesicle tethering and lipid mixing in vitro, which makes them suitable for the latter expansion mechanism. Ceramide (Cer) is a sphingolipid previously described to facilitate membrane fusion. Cer has also been related to macroautophagy modulation previously, although its specific role remains unclear. Moreover, the presence of sphingolipids in the AP has been suggested by recent experiments, increasing the relevance of Cer in macroautophagy. The present work has investigated the potential role that Cer could have on the proposed fusion of new vesicles to the nascent AP membrane. Interaction of purified ATG proteins with lipid vesicles of defined composition has been quantified using fluorescence spectroscopic techniques. Our results suggest that, if present, Cer could promote the vesicle tethering and leakage-free intervesicular lipid mixing induced by GABARAP and GABARAPL1, which would in turn mediate AP membrane expansion.

Keywords:  Autophagosome; Autophagy; Ceramide; LC3/GABARAP; Membrane fusion

DOI:  https://doi.org/10.1007/s00018-025-05811-9
Oncol Rep. 2025 Sep;pii: 113. [Epub ahead of print]54(3):

TRPML3‑mediated lysosomal Ca2+ release enhances drug sequestration and biogenesis, promoting osimertinib resistance in non‑small cell lung cancer.

Mi Seong Kim, Min Seuk Kim.

  Lysosomes and lysosomal Ca2+ play crucial roles in cellular homeostasis and drug resistance. The lysosomal Ca2+ channel transient receptor potential mucolipin 3 (TRPML3; also known as mucolipin‑3 or MCOLN3) is a key regulator of autophagy and membrane trafficking; however, its role in tyrosine kinase inhibitor (TKI) resistance remains unclear. The contribution of TRPML3 to osimertinib resistance in non‑small cell lung cancer (NSCLC) was therefore assessed. Using publicly available RNA sequencing data, including profiles from clinical samples before and after osimertinib treatment, TRPML3 expression was measured in lung adenocarcinoma (LUAD) tissues. Additionally, two‑dimensional cell culture of, and three‑dimensional spheroids derived from, NSCLC cell lines were used to elucidate roles of TRPML3 in drug resistance. TRPML3 expression was significantly upregulated in both LUAD tissues from patients with residual disease after osimertinib treatment, as well as in osimertinib‑resistant NSCLC cells. TRPML3 knockdown in resistant PC9 cells restored sensitivity to osimertinib and multiple TKIs; this was replicated in spheroid models. Mechanistically, osimertinib induced intracellular Ca2+ oscillations in PC9 cells via lysosomal Ca2+ release through TRPML3 rather than through TRPML1. In summary, the present findings suggest that elevated TRPML3 expression compensates for TRPML1 to maintain lysosomal acidity and biogenesis during TKI treatment, facilitating drug sequestration and resistance and identifying TRPML3 as a potential target for overcoming osimertinib resistance in NSCLC.

Keywords:  Ca2+ signaling; NSCLC; TRPML3; drug resistance; lysosome; osimertinib

DOI:  https://doi.org/10.3892/or.2025.8946
Curr Issues Mol Biol. 2025 Apr 23. pii: 297. [Epub ahead of print]47(5):

The Mechanical Role of YAP/TAZ in the Development of Diabetic Cardiomyopathy.

Jun-Xian Shen, Ling Zhang, Huan-Huan Liu, Zhen-Ye Zhang, Ning Zhao, Jia-Bin Zhou, Ling-Ling Qian, Ru-Xing Wang.

  Diabetic cardiomyopathy (DCM) begins with a subclinical stage featuring cardiac hypertrophy, fibrosis, and disrupted signaling. These changes, especially fibrosis and stiffness, often lead to clinical heart failure. The mechanism involves metabolic dysregulation, oxidative stress, and inflammation, leading to cardiac damage and dysfunction. During the progression of the disease, the myocardium senses surrounding mechanical cues, including extracellular matrix properties, tensile tension, shear stress, and pressure load, which significantly influence the pathological remodeling of the heart through mechanotransduction. At the molecular level, the mechanisms by which mechanical cues are sensed and transduced to mediate myocardial mechanical remodeling in DCM remain unclear. The mechanosensitive transcription factors YAP and TAZ fill this gap. This article reviews the latest findings of how YAP and TAZ perceive a wide range of mechanical cues, from shear stress to extracellular matrix stiffness. We focus on how these cues are relayed through the cytoskeleton to the nucleus, where they trigger downstream gene expression. Here, we review recent progress on the crucial role of YAP and TAZ mechanotransduction in the pathological changes observed in DCM, including myocardial fibrosis, hypertrophy, inflammation, mitochondrial dysfunction, and cell death.

Keywords:  Hippo; TAZ; YAP; diabetic cardiomyopathy; mechanotransduction

DOI:  https://doi.org/10.3390/cimb47050297
Adv Sci (Weinh). 2025 Jul 25. e15313

Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca2+ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.

Meng-Yuan Zhu, Yong-Jian Guo, Yu-Qi Zhu, Hong-Zheng Wang, Hai-di Wang, Hong-Yu Chen, Yue-Xin Jiang, Hui Li, Hui Hui.

  Inter-organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome-endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW-213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome-ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca2+-induced Ca2+ release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress-induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML-specific mechanisms when overexpressed. Subsequent studies using BALB/c xenograft models with wild-type and LIMP2-knockout THP1 cells, along with ICR mice toxicity models, confirmed LW-213's significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal-ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW-213 in managing tumor cell fate through modulating organellar interactions.

Keywords:  ERS; LIMP2; calcium crosstalk; lysosomal dynamics; membrane contact site; organelle interaction

DOI:  https://doi.org/10.1002/advs.202415313
J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.

Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.

  The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.

Keywords:  IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response

DOI:  https://doi.org/10.1016/j.jbc.2025.110504
Sci Signal. 2025 Jul 22. 18(896): eadp6006

Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.

Yan Sun, Abhishek Kumar Mishra, Vasanth Chanrasekhar, Michaela Door, Chase W Kessinger, Bing Xu, Peiyang Tang, Yunan Gao, Sarah Kamli-Salino, Katherine Nelson, Mirela Delibegovic, E Dale Abel, Jonanthan A Kirk, Maria I Kontaridis.

Cardiomyocytes (CMs) normally use fatty acid oxidation (FAO) as their primary energy source. In response to pathological stress, the substrate preference of CMs switches from FAO to glucose metabolism, leading to the development of heart failure. Obesity increases this pathological risk of cardiovascular disease. We focused on protein tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling, the abundance and activity of which are increased in brain, muscle, and adipose tissues in obese and/or diabetic animals and in obese human patients. We generated mice with CM-specific deficiency in PTP1B (PTP1Bfl/fl::ꭤMHCCre/+) to investigate the CM-specific role of PTP1B in response to cardiac dysfunction induced by high-fat diet (HFD) feeding. Although no physiological or functional cardiac differences were observed at baseline, PTP1Bfl/fl::ꭤMHCCre/+ mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis induced by HFD feeding. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased FAO and lipolysis but reduced glucose metabolism. Furthermore, phosphoproteomics analyses and mechanistic studies identified an axis involving the kinases PKM2 and AMPK downstream of PTP1B in the heart, which collectively acted to promote FAO and suppress lipogenesis. Together, these results suggest that CM-specific deletion of PTP1B prevents a substrate switch from FAO to glucose metabolism, protecting the heart against the development of HFD-induced cardiac hypertrophy and dysfunction.

DOI: https://doi.org/10.1126/scisignal.adp6006
Cardiovasc Diabetol. 2025 Jul 18. 24(1): 293

Cardiac digital twins: a tool to investigate the function and treatment of the diabetic heart.

Marina Strocchi, Daniel J Hammersley, Brian P Halliday, Sanjay K Prasad, Steven A Niederer.

  Diabetes increases the risk of cardiovascular disease (CVD) due to its multi-scale and diverse effects on cardiomyocyte metabolism and function, the circulation, and the kidneys. The complex relationship between organ systems affected by diabetes and associated comorbidities leads to challenges in estimating cardiovascular risk and stratifying optimal treatment strategies at the individual patient level. Most recently, sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists have been shown to offer substantial cardiac benefits. However, the direct or indirect mechanisms through which these agents protect the heart remain unclear, posing a challenge to patient selection. Amidst a growing burden of diabetes and increased therapeutic armamentarium, there is an important unmet need to develop more precise methods and technologies to understand the effects of diabetes and anti-diabetic treatment on the heart with faster timelines than conventional randomised controlled trials. Cardiac computational models could be used to improve our understanding of the cardiac changes in diabetes and to predict how a patient's heart will respond to anti-diabetic treatment. In this review, we provide an overview of current cardiac computational models to investigate the diabetic heart and the cardiac effects of anti-diabetic treatment. We discuss how multi-scale and multi-physics models could be applied in future to support the development of novel therapeutic approaches and further improve the treatment of diabetic patients with different CVD risk.

Keywords:  Anti-diabetic treatment; Cardiac computational model; Cardiovascular outcome trials; Diabetes; Digital twin; Heart; In-silico trials; Model

DOI:  https://doi.org/10.1186/s12933-025-02839-w