bims-lypmec 2025-07-06 papers

Life Sci. 2025 Jul 01. pii: S0024-3205(25)00465-5. [Epub ahead of print] 123830

Rab26-mediated lysosomal translocation of eEF1A alleviates myocardial hypertrophy and cardiac remodeling.

Yifan Tong, Yutong Li, Yaguang Bi, Yajiao Liu, Xiaoping Peng, Binfeng He, Xiang Wang.

BACKGROUNDS: Pathological myocardial hypertrophy and cardiac remodeling is a maladaptive response to stressors such as hypertension and genetic mutations, characterized by cardiomyocyte enlargement, fibrosis, cardiomyocyte apoptosis and impaired cardiac function. Rab26, a small GTPase, plays a crucial role in vesicle trafficking, secretion and apoptosis. However, its role in myocardial hypertrophy and cardiac remodeling remains unclear.
METHODS: Transverse aortic constriction (TAC) model was employed to induce myocardial hypertrophy and cardiac remodeling, with functional and histological assessments. Cardiac-specific Rab26 overexpression was achieved via AAV9-cTnT-Rab26 delivery, while Rab26 knockout was used for loss-of-function analysis. Molecular mechanisms were explored using protein interaction studies, fluorescence co-localization, and protease inhibition assays.
RESULTS: Our findings indicated a significant downregulation of RAB26 protein expression in the disease model, while its mRNA levels remained unaltered. Notably, cardiac-specific overexpression of Rab26 led to improved cardiac function, decreased cardiac fibrosis, suppressed myocardial hypertrophy and cardiomyocyte apoptosis. Furthermore, the knockout of Rab26 aggravated myocardial hypertrophy and cardiac remodeling. At the mechanistic level, Rab26 facilitates the lysosome translocation and degradation of eEF1A. Additionally, eEF1A silencing eliminated the protective effect of Rab26 on the heart. Comprehensive evaluation revealed the important role of the Rab26-eEF1A axis in mediating pathological myocardial hypertrophy and cardiac remodeling.
CONCLUSIONS: This study suggests that Rab26 prevents cardiac remodeling and dysfunction under pressure overload by promoting the lysosome translocation and degradation of eEF1A. Targeting the Rab26-eEF1A axis thus provides a potential strategy for preventing or reversing myocardial hypertrophy and cardiac remodeling.

Keywords: Cardiac remodeling; Heart failure; Myocardial hypertrophy; Rab26; eEF1A

DOI: https://doi.org/10.1016/j.lfs.2025.123830

Front Cell Dev Biol. 2025 ;13 1575571

Engine breakdown of lysosomes and related organelles and the resulting physiology.

Nina Bakker, Marlieke L M Jongsma, Jacques Neefjes.

Late endosomes/lysosomes (LE/Lys) and lysosome related organelles (LROs) move dynamically through cells which involves many levels of regulation. To reach their destination, they need to connect to the motor proteins dynein-dynactin, kinesin or myosin for long-range bidirectional transport along microtubules and short-range movement along actin filaments. This connection depends on various factors at the microtubule, including the MAP- and tubulin-code, as well as adaptors, Rab GTPases and effector proteins marking the LE/Lys and LRO membranes. Mutations affecting this transport results in defective LE/Lys or LRO cargo delivery often resulting in skin, neurological and/or immunological diseases. How LE/Lys and LRO transport is orchestrated and how it fails in disease states, will be discussed.

Keywords: disease; dynein; kinesin; lysosome-related organelles (LROs); lysosomes; microtubules; transport

DOI: https://doi.org/10.3389/fcell.2025.1575571

Int J Biol Sci. 2025 ;21(9): 3852-3866

APT1-derived depalmitoylation of CD36 alleviates diabetes-induced lipotoxicity in podocytes.

Juan Wang, Jijia Hu, Hongtu Hu, Qian Guan, Zijing Zhu, Qian Yang, Guohua Ding.

Cluster of Differentiation 36 (CD36), also known as scavenger receptor B2, plays a critical role in controlling podocyte lipid metabolism, mediating the onset and progression of diabetic kidney disease (DKD). However, the post-translational regulation of CD36 and its exact role in lipid transport within podocytes remain unclear. In this study, we elucidate the mechanism by which acyl-protein thioesterase 1 (APT1) depalmitoylates CD36 in podocytes. We reveal that APT1 interacts with CD36 and reduces its palmitoylation at Cys466 specifically, thereby promoting its trafficking from the plasma membrane to lysosomes for degradation. Diabetes-induced downregulation of APT1 redirects palmitoylated CD36 into the recycling pathway. Consequently, enhanced lipid uptake in podocytes leads to lipotoxicity. Conversely, APT1 overexpression mitigates lipid accumulation by enhancing lysosomal degradation and reducing plasma membrane-associated CD36. Our findings indicate that diabetes-induced APT1 deficiency promotes palmitoylated CD36 enrichment on plasma membranes through decreased APT1 expression, driving lipid overload and podocyte injury.

Keywords: APT1; CD36; Diabetic kidney disease; Lipotoxicity; Podocyte

DOI: https://doi.org/10.7150/ijbs.109220

iScience. 2025 Jul 18. 28(7): 112816

Genetically encoded and modular subcellular organelle probes reveal dysfunction in lysosomes and mitochondria driven by PRKN knockout.

Camille Goldman, Tatyana Kareva, Lily Sarrafha, Braxton R Schuldt, Abhishek Sahasrabudhe, Tim Ahfeldt, Joel W Blanchard.

Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosomes is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (genetically encoded and modular subcellular organelle probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN-knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provides critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.

Keywords: Cell biology; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2025.112816