bims-lypmec 2025-09-14 papers

Int J Mol Sci. 2025 Aug 26. pii: 8291. [Epub ahead of print]26(17):

Inorganic Silica Nanoparticles Increase Lysosomal Biology and Protease Activity.

Anastasiia O Syrocheva, Valentina I Gorbacheva, Vera S Egorova, Andrey A Zamyatnin, Alessandro Parodi, Ekaterina P Kolesova.

The use of nanoparticles has revolutionized drug delivery by enabling targeted and controlled therapeutic release. However, their interactions with intracellular organelles, particularly lysosomes, are not yet fully understood. This study delineates the differential effects of two widely used nanocarriers-mesoporous silica (MSNs) and albumin (ANPs) nanoparticles-on lysosomal biology, with a focus on the expression and activity of cathepsins (CtsB and CtsD), which are key proteases involved in protein degradation and maintaining cellular balance. These two types of nanoparticles, differing in their material and degradability, exhibit distinct behaviors inside the cell. We demonstrate that inorganic MSNs cause significant changes in lysosomal function by altering lysosomal content and cathepsin levels, without triggering lysosomal membrane permeabilization-a typical response to organic particle stress. In contrast, ANPs-which are susceptible to lysosomal cathepsin degradation-induce milder changes in cathepsin expression and maintain lysosomal integrity. Our results highlight that the composition of nanocarriers plays a pivotal role in modulating lysosomal protease activity and maintaining overall cellular homeostasis, highlighting the importance of these parameters in the rational design of drug delivery platforms.

Keywords: albumin nanoparticles; cathepsins; drug delivery; lysosomes; mesoporous silica nanoparticles; nanocarriers

DOI: https://doi.org/10.3390/ijms26178291

Autophagy. 2025 Sep 10.

Microautophagy: definition, classification, and the complexity of the underlying mechanisms.

Yasuyoshi Sakai, Christian Behrends, Ana Maria Cuervo, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Fulvio Reggiori.

Recently, rapid progress in the field of microautophagy (MI-autophagy) revealed the existence of multiple subtypes that differ in both intracellular membrane dynamics and molecular mechanisms. As a result, a single umbrella term "microautophagy" has become too vague, even creating some confusion among researchers both within and outside the field. We herein describe different subtypes of MI-autophagic processes and propose a systematic approach for naming them more accurately.

Keywords: Atg proteins; ESCRT proteins; lysosome; microautophagy; vacuole

DOI: https://doi.org/10.1080/15548627.2025.2559687

Sci China Life Sci. 2025 Sep 08.

Mitochondria-lysosome crosstalk in microbial infections.

Qianqian He, Tiantian Huang, Zhihui Chen, Zhou Sha, Haibo Wu.

Coordination between different organelles and metabolic cues is crucial for resistance to pathogen invasion. As the core of maintaining cellular metabolism and homeostasis, mitochondria and lysosomes cooperate in the immune responses and elimination of intracellular pathogens. Previous research has focused on the function of one or the other in isolation, ignoring their pervasive interplay. In this review, we discuss the intricate mechanism of mitochondria-lysosome crosstalk and point out the role of AMP-activated protein kinase (AMPK)-transcription factor EB (TFEB) axis in microbial infections. The crosstalk between mitochondria and lysosomes affects cellular key processes, such as autophagy and programmed death, which play an important role in microbial infections.

Keywords: MDVs; lysosomes; microbial infections; mitochondria; mitophagy

DOI: https://doi.org/10.1007/s11427-024-3037-1

Mol Biol Rep. 2025 Sep 10. 52(1): 881

Lysosome-dependent cell death: disease implications and potential therapeutic targets.

Ahequeli Gemingnuer, Rui Yin, Yan Liu, Yuan Tian, Xin Meng.

Lysosome-dependent cell death (LDCD) is a regulated form of cell death initiated by increased lysosomal membrane permeability, leading to the cytoplasmic release of lysosomal enzymes and subsequent cellular damage. Molecular mechanisms controlling LDCD include lysosomal membrane instability and lysosomal enzyme release, which together lead to cell damage. A more profound comprehension of these underlying mechanisms may reveal new therapeutic targets for diseases associated with lysosomal dysfunction. This crucial process is implicated in numerous pathological conditions, including neurodegenerative diseases, various types of cancer, cardiovascular disorders, and autoimmune diseases. Despite the considerable therapeutic implications of LDCD, recent years have witnessed a notable absence of comprehensive reviews addressing the exploration of LDCD-related therapeutic targets in disease management. This review systematically discusses the molecular pathways of LDCD, its role in disease pathogenesis, potential clinical biomarkers, and therapeutic interventions. This extensive endeavor aims to establish a robust foundation for researchers to explore the complexities of LDCD in greater depth and to propel drug discovery in this highly promising field.

Keywords: Cathepsins; Cell death pathways; Disease associations; Lysosomal membrane permeabilization; Lysosome-dependent cell death; Therapeutic target

DOI: https://doi.org/10.1007/s11033-025-10997-z

Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords: Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI: https://doi.org/10.1080/15548627.2025.2561073

J Mol Med (Berl). 2025 Sep 12.

Genetic deficiency of CCL5 exhibits the phenotypes of HFpEF and aggravates apoptotic cardiomyopathy in HFD-induced diabetic mice.

Jiung-Pang Huang, Kuan-Hsing Chen, Po-Shiuan Hsieh, Chao-Yu Kuo, Chao-Lan Yu, Li-Man Hung.

The chemokine C-C motif ligand 5 (CCL5) has been implicated in both metabolic dysfunction and cardiovascular diseases; however, its specific role in the pathophysiology of diabetic cardiomyopathy and heart failure remains incompletely understood. This study investigates the impact of CCL5 on the progression of diabetic cardiomyopathy and heart failure. A mouse model of obesity, insulin resistance, and diabetes was established using mice subjected to a high-fat diet (HFD). The genetic deletion of CCL5 was performed to evaluate the consequences of CCL5 deletion on metabolic parameters and cardiac function. CCL5 knockout mice subjected to a 20-week HFD exhibited resistance to metabolic complications, including obesity, hypercholesterolemia, hyperinsulinemia, and insulin resistance. However, CCL5 deletion led to the development of heart failure with preserved ejection fraction (HFpEF), characterized by cardiomyocyte hypertrophy, increased cardiac and plasma ANP and BNP expression, diastolic dysfunction, myocardial fibrosis, inflammation, and apoptosis. Additionally, CCL5 deficiency exacerbated HFD-induced TUNEL signaling and increased the expression of apoptosis-related genes and proteins, contributing to apoptotic cardiomyopathy in HFD-induced diabetic mice. Our findings suggest that physiological levels of CCL5 have a detrimental impact on the metabolic phenotype in DM mice, while simultaneously as a modulator on cardiac remodeling. CCL5 deficiency can lead to the development of HFpEF, suggesting its critical involvement in cardiac remodeling. Despite its dual role, CCL5 appears to play a significant modulator in both cardiac remodeling and diabetic metabolism. Targeting CCL5 may represent a novel therapeutic approach for mitigating metabolic disturbances while preserving cardiac function in diabetic cardiomyopathy. KEY MESSAGES: The physiological levels of CCL5 have a detrimental impact on the systemic metabolism in HFD-induced diabetic mice, while simultaneously representing a modulator on cardiac remodeling. Deficiency of CCL5 exhibits HFpEF phenotypes and aggravates apoptotic cardiomyopathy in DM mice. This article is the first to reveal the dual role of CCL5 in systemic metabolism and cardiac remodeling, and provides valuable insights in diabetic cardiomyopathy and heart failure, potentially informing future therapeutic strategies.

Keywords: Apoptotic cardiomyopathy; CCL5 KO; DM; HFpEF; Obesity

DOI: https://doi.org/10.1007/s00109-025-02579-0