bims-lypmec 2025-05-18 papers

J Cell Physiol. 2025 May;240(5): e70044

Lysosomes are essential organelles degrading a wide range of substrates, maintaining cellular homeostasis, and regulating cell growth through nutrient and metabolic signaling. A key vulnerability of lysosomes is their membrane permeabilization (LMP), a process tightly linked to diseases including aging, neurodegeneration, lysosomal storage disorders, and cardiovascular disease. Research progress in the past few years has greatly improved our understanding of lysosomal repair mechanisms. Upon LMP, cells activate multiple membrane remodeling processes to restore lysosomal integrity, such as membrane invagination, tubulation, lipid patching, and membrane stabilization. These repair pathways are critical in preserving cellular stress tolerance and preventing deleterious inflammation and cell death triggered by lysosomal damage. This review focuses on the expanding mechanistic insights of lysosomal repair, highlighting its crucial role in maintaining cellular health and the implications for disease pathogenesis and therapeutic strategies.

Keywords: Atg8ylation; CASM; ESCRT; Lysosomal repair; PITT; annexins; lysosomal membrane permeabilization; microlysophagy; stress granules

DOI: https://doi.org/10.1002/jcp.70044

Curr Obes Rep. 2025 May 14. 14(1): 43

Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders.

Lenny Yi Tong Cheong, Eka Norfaishanty Saipuljumri, Gavin Wen Zhao Loi, Jialiu Zeng, Chih Hung Lo.

PURPOSE OF REVIEW: Obesity is a global health crisis affecting individuals across all age groups, significantly increasing the risk of metabolic disorders such as type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular diseases. The World Health Organization reported in 2022 that 2.5 billion adults were overweight, with 890 million classified as obese, emphasizing the urgent need for effective interventions. A critical aspect of obesity's pathophysiology is meta-inflammation-a chronic, systemic low-grade inflammatory state driven by excess adipose tissue, which disrupts metabolic homeostasis. This review examines the role of autolysosomal dysfunction in obesity-related metabolic disorders, exploring its impact across multiple metabolic organs and evaluating potential therapeutic strategies that target autophagy and lysosomal function.
RECENT FINDINGS: Emerging research highlights the importance of autophagy in maintaining cellular homeostasis and metabolic balance. Obesity-induced lysosomal dysfunction impairs the autophagic degradation process, contributing to the accumulation of damaged organelles and toxic aggregates, exacerbating insulin resistance, lipotoxicity, and chronic inflammation. Studies have identified autophagic defects in key metabolic tissues, including adipose tissue, skeletal muscle, liver, pancreas, kidney, heart, and brain, linking autophagy dysregulation to the progression of metabolic diseases. Preclinical investigations suggest that pharmacological and nutritional interventions-such as AMPK activation, caloric restriction mimetics, and lysosomal-targeting compounds-can restore autophagic function and improve metabolic outcomes in obesity models. Autolysosomal dysfunction is a pivotal contributor to obesity-associated metabolic disorders , influencing systemic inflammation and metabolic dysfunction. Restoring autophagy and lysosomal function holds promise as a therapeutic strategy to mitigate obesity-driven pathologies. Future research should focus on translating these findings into clinical applications, optimizing targeted interventions to improve metabolic health and reduce obesity-associated complications.

Keywords: Autophagy function; Lysosomal acidification; Metabolic inflammation; Neurodegeneration; Neuroinflammation; Therapeutic strategies

DOI: https://doi.org/10.1007/s13679-025-00638-8

Aging Dis. 2025 Apr 22.

Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.

Yu Sun, Jin Wei, Shiyin Ma, Chang He, Liutao Sui, Xudong Pan, Xiaoyan Zhu.

Lysosomes are degradation centers and signaling hubs that in cells and play important roles in cellular homeostasis, development, and aging. Growing evidence has also implicated the role of lysosome-related mechanisms in the aging process. Meanwhile, the potential impact of lysosomal dysfunction on the production of inflammatory molecules, cellular metabolic status, and mitochondrial function is becoming increasingly significant. In this review, we provide a comprehensive overview of the physiological roles of lysosomes and their association with aging. At the cellular level, lysosomal dysfunction and cellular senescence show strong correlations. Herein, we elucidated the precise mechanisms by which lysosomal dysfunction contributes to various cellular physiological processes, as well as its potential implications in age-related hallmarks. More importantly, we discuss how lysosomal homeostasis is disrupted in several age-related diseases, including atherosclerosis, heart diseases, cancer, neurodegenerative diseases, metabolic disorders, and motor system diseases. Thus, a deeper understanding of lysosomal function may provide fundamental insights into human physiology and age-related diseases. Furthermore, these discoveries emphasize the role of the lysosome in the development of novel therapeutic strategies.

DOI: https://doi.org/10.14336/AD.2025.0275

Cardiovasc Pathol. 2025 May 10. pii: S1054-8807(25)00027-4. [Epub ahead of print] 107742

The anti-atherosclerosis effect and molecular mechanism of AMPKα1 by polarizing monocytes to an M2 phenotype via cell-intrinsic lysosomal lipolysis.

Jing Wang, Yahui Zhang, Caixing Cao, Jiale Hua, Li Xing, Changxin Wu.

Regulating the differentiation of monocytes into M2 macrophages can promote the regression of Atherosclerosis (AS) plaque. However, the key molecules regulating the differentiation of monocytes to M2 are unknown. In this study, we reported that adenosine-activated protein kinase α1 (AMPKα1) plays an anti-AS role by polarizing monocytes to an M2 phenotype via promoting fatty acid oxidation (FAO). AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to provide fatty acids for FAO. Furthermore, AMPKα1 can induce lysosomal biogenesis and enhance lipolysis by promoting the transcription factor EB (TFEB) expression and facilitating TFEB nuclear translocation. In conclusion, AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to produce fatty acids, which may represent a mechanism to promote FAO and inflammatory monocytes differentiation towards M2 phenotype.

Keywords: M2 macrophage; adenosine-activated protein kinase α1; atherosclerosis; lysosomal acid lipase; lysosome; monocytes; transcription factor EB

DOI: https://doi.org/10.1016/j.carpath.2025.107742

J Cell Biol. 2025 Jul 07. pii: e202504129. [Epub ahead of print]224(7):

Atg9 is a conserved regulator of lysosome repair.

Ruoxi Wang, Eric H Baehrecke.

The ATG9 transmembrane protein scrambles lipids to regulate phagophore formation during autophagy. Two recent studies from Peng et al. (https://doi.org/10.1083/jcb.202411092) and De Tito et al. (https://doi.org/10.1101/2024.07.23.604321) identify ATG9 as a conserved regulator of lysosome repair in Caenorhabditis elegans and human cells, but differences in repair mechanisms exist between these taxa.

DOI: https://doi.org/10.1083/jcb.202504129

Cell Rep. 2025 May 12. pii: S2211-1247(25)00454-1. [Epub ahead of print]44(5): 115683

TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.

Raffaele Nicastro, Marie-Pierre Péli-Gulli, Marco Caligaris, Malika Jaquenoud, Ladislav Dokládal, Josephine Alba, Farida Tripodi, Benjamin Pillet, Melanie Brunner, Michael Stumpe, Kenji Muneshige, Riko Hatakeyama, Jörn Dengjel, Claudio De Virgilio.

The eukaryotic target of rapamycin complex 1 (TORC1) kinase is a homeostatic regulator of growth, integrating nutritional cues at the endolysosomal compartment. Amino acids activate mammalian TORC1 (mTORC1) through the Rag GTPases that recruit it to lysosomes via a short domain within the mTORC1 subunit Raptor. Intriguingly, this "Raptor claw" domain is absent in Kog1, the Raptor ortholog in yeast. Instead, as we show here, yeast utilizes the fungal-specific Tco89 to tether TORC1 to active Rag GTPases. This interaction enables TORC1 to precisely calibrate the activity of the S6K1-related effector kinase Sch9 in response to amino acid availability. TORC1 stabilizes Tco89 by phosphorylation, and its inactivation causes swift Tco89 proteolysis, provoking a redistribution of TORC1 from the vacuole to signaling endosomes and its spatial separation from Sch9. Thus, TORC1 not only operates in spatially distinct subcellular pools but also controls its own quantitative distribution between these pools to economize energy resources under fluctuating nutrient conditions.

Keywords: CP: Cell biology; CP: Molecular biology; Rag GTPases; TORC1; Tco89; amino acid signaling; growth control; target of rapamycin complex 1

DOI: https://doi.org/10.1016/j.celrep.2025.115683

J Physiol. 2025 May 11.

14-3-3 proteins: Regulators of cardiac excitation-contraction coupling and stress responses.

Heather C Spooner, Rose E Dixon.

14-3-3 proteins are highly conserved proteins that regulate numerous cellular processes mostly through phosphorylation-dependent protein-protein interactions. In the heart 14-3-3 proteins play critical roles in cardiac conduction pathways, excitation-contraction (EC) coupling, development and stress responses. This review summarizes the current understanding of cardiac 14-3-3 regulation and function, with particular emphasis on its role in ion channel regulation and β-adrenergic signalling. We discuss how 14-3-3 proteins act through three main mechanisms - masking, clamping, and scaffolding - to regulate target proteins, including Cx43, CaV1.2, NaV1.5, and various potassium channels. The seven mammalian 14-3-3 isoforms display distinct but overlapping functions, with tissue-specific expression patterns and isoform-specific regulation through phosphorylation and dimerization. Recent work has revealed 14-3-3's importance in cardiac development and stress responses, where it generally serves a cardioprotective role. However in some pathological contexts such as ischaemia-reperfusion injury, 14-3-3 can be detrimental. We highlight emerging themes in cardiac 14-3-3 biology, including its role in prolonging β-adrenergic signalling. Understanding the complex regulation of cardiac 14-3-3 and its numerous targets presents both opportunities and challenges for therapeutic development.

Keywords: 14‐3‐3; EC coupling; cardiac stress; cardiovascular physiology; ion channel clustering; ion channel regulation

DOI: https://doi.org/10.1113/JP288566