bims-lypmec 2026-07-05 papers

Cell. 2026 Jul 01. pii: S0092-8674(26)00701-4. [Epub ahead of print]

Co-option of lysosomal machinery shapes the evolution of the intracellular photosymbiosis supporting coral reefs.

Shumpei Maruyama, Catherine F Henderson, Natalie Swinhoe, Griffin P Kowalewski, Emily K Meier, Ty R Engelke, Phillip A Cleves.

Endosymbiosis has spurred the evolution of new organelles across life. Corals and other cnidarians have repeatedly evolved an organelle, called the symbiosome, which houses intracellular algal symbionts. However, the molecular mechanisms enabling this repeated evolution remain unclear. Using the sea anemone Aiptasia, we generated a high-quality proteome of the symbiosome, revealing protein trafficking mechanisms and the types of biomolecules exchanged during symbiosis. Symbiosomal enrichment of lysosomal proteins, visualization of lysosomal fusion, and reduced symbiosis following knockdown of lysosomal genes indicate that the symbiosome functions through extensive co-option of lysosomal proteins. We identified a symbiosomal bicarbonate/sulfate transporter, SLC26A11, and showed through CRISPR/Cas9 mutagenesis that this lysosomal transporter is required for symbiosis in Aiptasia and a reef-building coral. Together, these findings reveal that corals and anemones have repeatedly co-opted lysosomal proteins to concentrate carbon and shuttle metabolites to support photosymbiosis, providing a relatively simple path for the repeated evolution of new photosymbioses.

Keywords: coral; endosymbiosis; evolution; lysosome; phagosome; photosymbiosis; symbiosis; symbiosome

DOI: https://doi.org/10.1016/j.cell.2026.06.015

Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2514112123

A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.

Jessica Lawrence, Vineet Vinay Kulkarni, Chan Lek Tan, Marinella Callow, Yves Juste, Dewakar Sangaraju, Mike Costa, Baris Bingol.

Mutations in the GBA1 gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of α-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson's to boost the activity of this enzyme in lysosomes.

Keywords: Gaucher disease; Parkinson’s disease; functional genomics; lipid homeostasis; lysosomes

DOI: https://doi.org/10.1073/pnas.2514112123

Mater Today Bio. 2026 Aug;39 103384

Lysosomal aggregation of iron nanoparticles guided by multistage transformation induces potent ferroptosis.

Huan Liang, Runyu Hu, Qingqing Lu, Jun Zhang, Bingyan Lu, Jie Yang.

Ferroptosis, a cell death form driven by lipid peroxidation accumulation via iron-dependent Fenton reaction, has attracted substantial attention in cancer therapy. This process is strictly dependent on iron ion concentration and environmental acidity. However, the relatively weak acidity in the tumor cytoplasm may significantly impair the Fenton catalytic activity of endocytosed iron-based nanoparticles. Inspired by the intrinsic acidic vesicular compartments of tumoral lysosomes, a multistage size-switching strategy is proposed to effectively target the optimal "battlefields" for iron-based materials. Through rational engineering, nanotransformers (NTF) integrated with collagenase (CLG) achieve targeted disassembly for deep tumor penetration and lysosomal aggregation to sustain Fenton catalytic activity. Enlarged iron depots in lysosomes prevent exocytosis, ensuring prolonged catalytic generation of lipid peroxidation species to initiate and amplify ferroptosis, ultimately inducing lysosomal membrane permeabilization and altered organelle functions. Further analysis reveals that iron nanoparticle lysosomal aggregation-mediated ferroptosis can effectively trigger immunogenic cell death and elicit robust antitumor immune responses. This work demonstrates the potential of well-designed multistage size-switchable nanotransformers in cancer treatment, representing a paradigm shift in advancing iron-based nanoparticle-mediated ferroptosis therapy.

Keywords: Fenton reaction; Ferroptosis; Immunogenic cell death; Iron nanoparticles; Lysosomal aggregation

DOI: https://doi.org/10.1016/j.mtbio.2026.103384

J Geriatr Cardiol. 2026 May 28. 23(5): 275-283

Ketogenic diet, cardiometabolic diseases and aging.

Giuseppe Cioffi, Gianluigi Cuomo, Raffaele Carluccio, Crescenzo Testa, Anna Di Lorenzo, Luigi De Vito, Valentina Parisi, Maddalena Conte, Dario Leosco, Francesco Giallauria.

The ketogenic diet (KD), characterized by a high-fat, moderate-protein, and low-carbohydrate macronutrient composition, has gained growing interest as a potential nutritional approach to cardiometabolic diseases and aging. Emerging evidence suggests that ketone bodies, particularly β-hydroxybutyrate, act not only as alternative energy substrates but also as signaling molecules that influence vascular, metabolic, and epigenetic pathways. This review summarizes current knowledge on the cardiovascular and metabolic implications of KD, emphasizing endothelial function, cardiac energy metabolism, lipid profile, and blood pressure regulation. Experimental and clinical data indicate that KD enhances endothelial antioxidant capacity via Nrf2 activation and eNOS upregulation, reduces cellular senescence, and modulates epigenetic regulators such as histone β-hydroxybutyrylation and SIRT1. In heart failure, acute ketone supplementation improves cardiac output and energetics, while chronic adherence to KD may impair hepatic ketogenesis and lipid homeostasis, potentially offsetting its benefits. Evidence in hypertension and dyslipidemia remains controversial, with short-term improvements often contrasted by long-term elevations in LDL cholesterol and arterial stiffness. In patients with type 2 diabetes, KD promotes glycemic control and insulin sensitivity, yet the sustainability and cardiovascular safety of prolonged use are uncertain. Overall, KD represents a promising but complex therapeutic tool whose efficacy depends on individual metabolic context, diet composition, and duration. A balanced, intermittent, or cyclic ketogenic approach may offer a safer strategy to harness its cardiometabolic and anti-aging benefits.

DOI: https://doi.org/10.26599/1671-5411.2026.05.005

Circ Res. 2026 Jul 02.

Mitochondrial STING Governs Glycolytic Reprogramming in Diabetic Cardiomyopathy.

Shiwu Zhang, Dechao Zhao, Mengyi Wang, Xiaorong Shen, Fan Yang, Zhen Tian, Haining Du, Fanghao Lu, Xueya Zhang, Heyu Chen, Jiaxin Kang, Mingjie Dong, Denis V Abramochkin, Huitao Fan, Jinwei Tian, Bo Yu, Shuijie Li, Weihua Zhang.

BACKGROUND: Diabetic cardiomyopathy, a severe complication of diabetes, is marked by mitochondrial dysfunction, metabolic inflammation, and progressive cardiac impairment. Although STING (stimulator of interferon genes) is well recognized as a central mediator of innate immunity, its noncanonical role in metabolic regulation and mitochondrial dynamics in the diabetic heart remains largely unexplored.
METHODS: To elucidate the role of STING in diabetic cardiac remodeling, we used single-cell RNA sequencing, echocardiography, and transmission electron microscopy in both genetic (db/db) and chemically induced (high-fat diet [HFD] plus streptozotocin, HFD/streptozotocin) diabetic mouse models. STING knockout mice and primary neonatal mouse cardiomyocytes were used for mechanistic investigations and functional validation. Mitochondrial respiration and glycolytic flux were assessed using Seahorse extracellular flux analysis. Posttranslational modifications of STING, including S-palmitoylation and S-sulfhydration, were evaluated via acyl-biotin exchange and biotin-switch assays, respectively. ENO1 (enolase 1) enzymatic activity was measured in vitro to assess glycolytic reprogramming. Furthermore, 13C-glucose tracing-based targeted metabolomics was performed to quantify cardiac metabolic flux in db/db mice. Glycolytic metabolites, including lactate and pyruvate, were quantified in cardiac tissues and cultured cardiomyocytes to assess glycolytic activity.
RESULTS: Exposure to high-palmitate conditions induced mitochondrial DNA leakage, thereby activating the cGAS-STING signaling pathway in cardiomyocytes. Mechanistically, STING underwent aberrant translocation to mitochondria, where it interacted with the outer membrane protein TOM (translocase of outer mitochondrial membrane) 40 to impair mitochondrial protein import and disrupt mitochondrial homeostasis. In addition, mitochondrial STING functioned as a scaffold to recruit and activate the glycolytic enzyme ENO1, thereby enhancing its enzymatic activity, accelerating glycolytic flux, and promoting lactate accumulation in diabetic cardiac tissues. Notably, diabetes-associated depletion of endogenous hydrogen sulfide reduced S-sulfhydration of STING at Cys88/91, facilitating its S-palmitoylation and mitochondrial localization. Genetic ablation of STING or pharmacological restoration of hydrogen sulfide levels with GYY4137 effectively rescued mitochondrial dysfunction, decreased lactate overproduction, and preserved cardiac contractile performance in diabetic mice.
CONCLUSIONS: These findings identify STING as a spatial immunometabolic modulator that bridges mitochondrial dysfunction with metabolic imbalance in diabetic cardiomyopathy. Enhancing STING S-sulfhydration or targeting its palmitoylation through hydrogen sulfide-based interventions represents a promising therapeutic strategy for the treatment of diabetic cardiomyopathy.

Keywords: diabetic cardiomyopathies; inflammation; metabolism; mitochon dria; streptozotocin

DOI: https://doi.org/10.1161/CIRCRESAHA.125.327867