bims-lycede 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

Microscopy (Oxf). 2025 May 13. pii: dfaf023. [Epub ahead of print]

Discovery of Golgi Membrane-associated Degradation Pathway, GOMED: A Focus on 15 Years of Ultrastructural Analyses.

Satoko Arakawa, Hirofumi Yamaguchi, Shigeomi Shimizu.

In this review, we focus on the ultrastructural characteristics of the Golgi membrane-associated degradation (GOMED) pathway, which have been clarified by electron microscopy and highlight recent advances in the elucidation of its molecular mechanism and physiological roles. The discovery of GOMED, an Atg5/Atg7-independent degradation pathway that differs from canonical autophagy in membrane origin, stimuli, and substrate specificity, has substantially expanded our understanding of intracellular degradation systems. In 2009, we identified GOMED as a novel, evolutionarily conserved autophagic pathway and demonstrated its role in intracellular degradation across eukaryotes, from yeast to mammals. We identified the conserved protein Hsv2/Wipi3 as an essential GOMED protein, which translocates to the trans-Golgi upon induction and remodels Golgi membranes into cup-shaped structures that engulf cytoplasmic components for lysosomal degradation. These processes contribute to organelle and secretory granule turnover, as well as mitochondrial clearance during erythroid differentiation. Moreover, neuronal-specific ablation of Wipi3 in mice causes severe cerebellar degeneration, implicating GOMED in tissue development and homeostasis. As these mechanisms are associated with diseases, such as neurodegenerative disorders and cancer, GOMED mechanisms should also be considered when establishing therapeutic strategies for these diseases.

Keywords: Autophagy; GOMED; Golgi; Mitophagy; Neurodegeneration; Wipi3

DOI: https://doi.org/10.1093/jmicro/dfaf023

J Agric Food Chem. 2025 May 15.

Enhanced SIRT1-TFEB Interaction Promotes Lysosome Biogenesis and Autophagy by Reducing TFEB Acetylation: Revealing the Enterotoxicity Disparity of Deoxynivalenol and T-2 Toxin.

Qiang Xu, Ruqin Lin, Tianqing Jiang, Luyu Deng, Yuting Wu, Qianqian Yuan, Xueying Qi, Peiqiang Mu, Jun Jiang, Yiqun Deng, Jikai Wen.

Multiple environmental factors contribute to digestive system damage caused by food contamination in both humans and animals. Mycotoxins, such as deoxynivalenol (DON) and T-2 toxin, have emerged as the most significant factors due to their extensive contamination and difficulty in removal. Transcription factor EB (TFEB) serves as a crucial transcriptional regulator governing lysosomal biogenesis and autophagy, a lysosomal-driven degradation system that safeguards cells against harmful stressors. However, little is known about whether the post-translational modification of TFEB affects autophagy activity, which could explain the toxicity disparity between DON and T-2 toxin. Here, we discovered that T-2 toxin induces excessive autophagy by significantly reducing TFEB acetylation, whereas DON surprisingly inhibits autophagy activity via maintaining high TFEB acetylation, which impairs lysosomal biogenesis, thereby boosting their respective toxicity. Mechanically, the T-2 toxin decreases TFEB acetylation via enhanced SIRT1-TFEB interaction and SIRT1 deacetylase activity, while DON maintains high TFEB acetylation by reversing the process. Together, our study revealed that the acetylation state of TFEB mediated by SIRT1 alters autophagy phenotypes in intestinal cells, shedding light on the various toxicological mechanisms and an important target of DON and T-2 toxin.

Keywords: SIRT1; T-2 toxin; TFEB; acetylation; autophagy; deoxynivalenol; lysosome

DOI: https://doi.org/10.1021/acs.jafc.5c01854

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