bims-lypmec 2026-03-29 papers

Trends Cell Biol. 2026 Mar 25. pii: S0962-8924(26)00033-4. [Epub ahead of print]

Repair condensates and lipid domains in lysosome integrity.

Lysosomes are sophisticated signaling hubs whose function depends on membrane integrity. A breach of this barrier, known as lysosomal membrane permeabilization, triggers inflammation and cell death, driving pathologies from lysosomal storage disorders to neurodegeneration. Cells counter membrane damage with diverse repair mechanisms, including endosomal sorting complexes required for transport machinery, sphingomyelin scrambling, annexin-mediated scaffolding, lipid transport, and stress granule plugging. This diversity suggests singular strategies are insufficient, posing an 'orchestration challenge' regarding precise initiation, spatial organization, and temporal coordination. This opinion article proposes that biomolecular condensation, initiated by damage cues, acts as a primary organizing principle. We suggest lysosomal injury nucleates de novo 'repair condensates' that stabilize compromised membranes and serve as recruitment and organizational hubs for repair machinery.

Keywords: biomolecular condensates; lipids; lysophagy; lysosomes; membrane damage

DOI: https://doi.org/10.1016/j.tcb.2026.03.002

Int J Mol Sci. 2026 Mar 17. pii: 2740. [Epub ahead of print]27(6):

Lipotoxicity in Diabetic Cardiomyopathy: Molecular Basis and Emerging Therapeutic Targets.

Yihua Han, Xinyi Chen, Oveena Fonseka, Wei Liu.

Diabetic cardiomyopathy (DbCM) is an important contributor to heart failure (HF) in diabetes, occurring independently of other cardiovascular risk factors. Accumulating evidence demonstrates that cardiac lipotoxicity is a key driver of the onset and progression of DbCM and HF. Myocardial lipid homeostasis is coordinated by multiple transcriptional regulations, signaling pathway activation, and endoplasmic reticulum-mediated management involved in lipid metabolism. In DbCM, unbalanced fatty acid (FA) influx, handling, storage, and utilization initiates lipid overload, accumulation of toxic lipid intermediates (e.g., diacylglycerols and ceramides), and activation of maladaptive response. Notably, these lipid intermediates amplify reactive oxygen species (ROS) generation, which serves as a critical link between lipotoxic signaling and mitochondrial dysfunction by promoting electron leak, mitochondrial damage, and activation of inflammatory and cell-death pathways. These processes converge on adverse remodeling and contractile impairment, accelerating DbCM progression. This review integrates mechanistic and translational evidence linking dysregulated lipid handling to DbCM and discusses the potential therapeutic strategies that target lipid abnormalities.

Keywords: cell metabolism; diabetes; diabetic cardiomyopathy; heart failure; lipid metabolism; lipotoxicity

DOI: https://doi.org/10.3390/ijms27062740

Cell Death Dis. 2026 Mar 23.

SIRT1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis.

Yu Duan, Yingchun Luo, Xuejie Han, Hui Yu, Hanwen Liu, Yun Zhou, Yunlong Gao, Qian Xu, Ying Wei, Ruoxin Min, Yong Hong, Xuanrui Ji, Haibo Jia, Yue Li, Yun Zhang.

Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases. The role of ferroptosis in age-related HF remains unclear. Here, we show that aged rats exhibit impaired cardiac function accompanied by hallmark features of ferroptosis, including reduced glutathione peroxidase 4 (GPX4) expression and excessive lipid peroxidation. Consistently, cardiomyocyte-specific GPX4 knockout mice develop exacerbated cardiac ferroptosis and pronounced cardiac dysfunction. Iron overload further aggravates ferroptotic injury and cardiac dysfunction in aged rats, whereas pharmacological inhibition of ferroptosis markedly alleviates these effects. Conversely, cardiomyocyte-specific overexpression of GPX4 via rAAV9 attenuates ferroptosis and preserves cardiac function in D-galactose-induced aging mice. Proteomic analysis identifies hydroxyacyl-CoA dehydrogenase subunit A (HADHA) as a key protein markedly downregulated in aging hearts, particularly under iron overload. Mechanistically, HADHA deficiency induces mitochondrial dysfunction and excessive reactive oxygen species production, leading to glutathione depletion, GPX4 suppression, and subsequent ferroptosis. Accordingly, cardiomyocyte-specific knockdown of HADHA in young mice recapitulates ferroptosis-associated cardiac remodeling, which is reversed by ferrostatin-1 treatment. Furthermore, we identify SIRT1 (sirtuin 1) as an upstream regulator of HADHA during cardiac aging. Reduced SIRT1 expression in aging hearts suppresses HADHA transcription through inhibition of GATA4. Importantly, both cardiomyocyte-specific SIRT1 overexpression via rAAV9 in D-galactose-induced aging mice and pharmacological SIRT1 activation by resveratrol in aging rats restore HADHA expression, suppress ferroptosis, and protect against HF. Collectively, these findings establish ferroptosis as a critical contributor to age-related HF and identify the SIRT1-GATA4-HADHA axis as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41419-026-08634-z

Methods Enzymol. 2026 ;pii: S0076-6879(26)00011-X. [Epub ahead of print]728 327-345

Real-time measurement of the ATG8 lipidation reaction by fluorescence spectroscopy.

Wenxin Zhang, Sharon A Tooze, Taki Nishimura.

Autophagy is a highly conserved intracellular degradation pathway, in which damaged organelles and/or dysfunctional cytosolic components are enveloped via double-membraned autophagosomes and subsequently delivered to lysosomes for degradation. The ubiquitin-like ATG8 family proteins (LC3s and GABARAPs) are covalently conjugated to phosphatidylethanolamine (PE) on autophagic membranes via ubiquitin-like conjugation systems, a process known as ATG8 lipidation. Lipidated ATG8 is the most widely used membrane marker for autophagosomes, and its flux is commonly used as a readout for autophagy activity. In vitro reconstitution of the ATG8 lipidation reaction is well-established, and the end-point reaction is typically resolved by SDS-PAGE. This endpoint readout is not suitable to monitor the kinetics of this reaction, and tools to study this process have been lacking. Here, we describe a real-time assay to measure the ATG8 lipidation reaction. This approach not only reveals the subsequential formation of covalently bound intermediates of ATG8 with the E1 (ATG7) and E2 (ATG3) enzymes, as well as ATG8-PE itself, but also provides insights into the interaction interface of ATG8 with proteins and membranes during the conjugation reaction.

Keywords: 3-diazol-4-yl (NBD); 7-nitrobenz-2-oxa-1; ATG8 lipidation; Autophagy; Fluorescence spectroscopy; Liposomes; Site-specific labeling; in vitro reconstitution

DOI: https://doi.org/10.1016/bs.mie.2026.01.011