bims-lypmec 2026-07-26 papers

Curr Biol. 2026 Jul 20. pii: S0960-9822(26)00655-X. [Epub ahead of print]36(14): R807-R820

Global cellular responses to lysosomal damage.

Lysosomes are membrane-bound organelles that orchestrate a wide range of cellular processes, including degradation, metabolism, signaling, gene regulation and quality control, while interacting with other organelles, thereby profoundly shaping cellular homeostasis and fate. Lysosomal membrane integrity is highly vulnerable to a broad spectrum of physiological and pathological insults, acting as both a cause and a consequence of diverse human conditions, including neurodegeneration, cancer, infectious disease and aging. Understanding the mechanisms by which cells respond to lysosomal damage is therefore of critical importance. Recent studies have revealed that cells deploy sophisticated damage response mechanisms locally to repair, remove, and replace damaged lysosomes. In contrast, how local lysosomal damage triggers global cellular responses is only beginning to be understood. This review summarizes recent conceptual advances in global cellular responses to lysosomal damage, encompassing translational, metabolic and transcriptional adaptations, and highlights their crucial roles in restoring cellular homeostasis and shaping outcomes in health and disease.

DOI: https://doi.org/10.1016/j.cub.2026.05.050

Nat Cell Biol. 2026 Jul 20.

Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.

Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.

Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.

DOI: https://doi.org/10.1038/s41556-026-02010-x

J Biochem. 2026 Jul 24. pii: mvag058. [Epub ahead of print]

Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.

Natsumi Sakata, Takaaki Akaike, Hozumi Motohashi.

Supersulfides, a class of catenated sulfur-containing biomolecules, are increasingly recognized as key regulators of redox signaling, mitochondrial function, and inflammatory responses. Recent evidence suggests that lysosomes, central organelles for intracellular degradation and nutrient sensing, are closely linked to supersulfide metabolism through lysosomal acidification, cysteine metabolism, and autophagy. Conversely, supersulfides modulate lysosomal activity and inflammatory responses. This review summarizes recent progress in supersulfide biology and lysosomal regulation and discusses evidence supporting functional interactions between these systems. We propose the lysosome-supersulfide axis as a new concept in cellular homeostasis and metabolic regulation.

Keywords: Amino acids; autophagy; cysteine; lysosome; supersulfides

DOI: https://doi.org/10.1093/jb/mvag058

Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00781-3. [Epub ahead of print]45(7): 117703

TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.

Jiamin Huang, Yayu Wang, Yudong Xu, Yanan Wei, Xiang Yin, Junling Li, Yu Zeng, Meiting Chen, Canjun Li, Li Wang, Xiaomei Li, Lili Qu, Chunlei Cang.

Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

Keywords: CLN7; CP: molecular biology; ERK; HSP90; TTYH3; autophagy; chloride conductance; lysosome; lysosome fusion; mTOR; senescence

DOI: https://doi.org/10.1016/j.celrep.2026.117703

Nat Cell Biol. 2026 Jul 20.

Borrowed scissors for lysosome fission.

Shawn M Ferguson.

DOI: https://doi.org/10.1038/s41556-026-02028-1

Circulation. 2026 Jul 21. 154(3): 223-239

Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.

BACKGROUND: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.
METHODS: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate Acly in cardiomyocytes of Myh6-Cas9 mice. In vivo positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to Acly knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.
RESULTS: We observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Using CRISPR/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry-based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac Idh1 deletion improved cardiac function and energy provision, reducing YAP phosphorylation and restoring downstream YAP signaling.
CONCLUSIONS: Our findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.

Keywords: ATP-dependent citrate lyase; cardio-oncology; metabolism; systems biology

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.076453