bims-lypmec 2026-09-06 papers

Redox Biol. 2026 Sep 01. pii: S2213-2317(26)00377-0. [Epub ahead of print]97 104378

TLDc proteins: Stress-responsive nexus regulators of redox signaling, V-ATPase dynamics, and organellar crosstalk in neurodegeneration.

Mohammad Sajid Ghufran, Priyanka Soni, Bobby Thomas.

Many age-related neurodegenerative disorders are marked by progressive defects in cellular energy metabolism and protein homeostasis that converge on mitochondrial and lysosomal dysfunction. TLDc domain-containing proteins, such as OXR1, NCOA7, and related family members, have emerged as crucial modulators of organellar physiology and cellular stress responses. Growing evidence indicates that TLDc proteins physically interact with vacuolar ATPases (V-ATPases) to modulate their assembly and catalytic activity, linking TLDc function directly to the maintenance of lysosomal and Golgi lumen pH. This organellar pH homeostasis, in turn, is fundamental to intracellular iron handling and metabolic regulation, processes essential for mitochondrial bioenergetics, lysosomal functions, and cellular viability. Lysosomes maintain an acidic lumen via V-ATPase proton pumping, counterbalanced by specific ion channels, including TMEM175. This acidic environment is required for ferric iron reduction and subsequent release into the cytosol; when acidification fails, cells develop cytosolic iron deficiency, mitochondrial defects, pseudohypoxia via HIF-1α activation, and inflammation. Conversely, iron flux from lysosomes to mitochondria depends on acidic conditions and direct organelle contact, as exemplified by BDH2-driven siderophore transport, a V-ATPase-dependent but not TLDc-regulated process, which supports mitochondrial bioenergetics and sustains lysosomal acidity. Iron and pH dysregulation synergize to drive ferroptosis, lipid peroxidation, and neurotoxicity. Emerging studies link lysosomal deacidification and iron dyshomeostasis to the pathogenesis of major neurodegenerative diseases. These mechanisms collectively shape neuronal resilience, survival, and aging trajectories. This review integrates recent insights into how TLDc proteins coordinate organellar pH regulation and iron homeostasis and discusses how disruption of these interconnected pathways contributes to age-related neurodegeneration.

Keywords: Lysosomal dysfunction; NCOA7; OXR1; Oxidative stress; TBC1D24; TLDc

DOI: https://doi.org/10.1016/j.redox.2026.104378

Commun Biol. 2026 Aug 31. pii: 1152. [Epub ahead of print]9(1):

SARS-CoV-2 Delta variant-specific ORF3a mutations destabilize lysosomal homeostasis to trigger lysosomal damage-mediated cell death.

Ayushi Amin Dey, Sanchita Mishra, Vigneshwar Reddy Ashireddygari, Bharadwaj Vemparala, Anantika Chandra, Disha Jain, Narendra M Dixit, Prasad Tammineni, Sannula Kesavardhana.

The variants of concern (VOCs) of SARS-CoV-2 emerged independently and became dominant globally at different times. Despite the emergence of multiple VOCs, the Delta variant of SARS-CoV-2 showed heightened pathogenicity and unprecedented mortality. However, the Delta variant specific mechanisms underlying its increased pathogenicity are unclear. Here, we show that variations in SARS-CoV-2 ORF3a correlate with the pathogenic potential of VOCs and drive Delta variant-specific lysosomal damage that activates inflammatory cell death. ORF3a from the Delta variant shows unique mutational patterns distinct from other SARS-CoV-2 VOCs. ORF3a-specific phylogenetic analysis reveals noticeable differences in the evolutionary trajectories of VOCs, likely reflective of their pathogenic relatedness. Unlike the Omicron variant and the ancestral Wuhan strain, Delta-specific ORF3a mutations promotes robust lysosomal damage, peripheral distribution, and membrane localization with no apparent effect on viral titers. Furthermore, Delta ORF3a mutations-induced lysosomal damage promotes both apoptosis and necroptosis activation in human cells. Structurally, these Delta variant-specific mutations appear to stabilize the ORF3a oligomers through helical packing and formation of a non-native disulfide bond, possibly facilitating their lysosomal association and damage. Overall, our observations indicate that ORF3a disrupts lysosomal homeostasis and triggers cell death, suggesting Delta-variant-specific regulation of cell fate and inflammation-associated pathogenesis.

DOI: https://doi.org/10.1038/s42003-026-10801-z

Nat Commun. 2026 Aug 06. pii: 9484. [Epub ahead of print]17(1):

Glycoprotein-induced phase separation drives unconventional secretion of galectin-3.

Zihan Zhao, Zhen He, Hongming Gu, Andong Zhou, Yibing Wang, Zhaoyi Liang, Jie Geng, Xuejiao Xu, Menghui Wang, Chunyao Li, Yuying Fan, Hairong Cheng, Lin Sun, Kevin H Mayo, Avraham Raz, Guihua Tai, Yifa Zhou.

The mechanism of unconventional protein secretion remains an unresolved issue. Here, we describe an unconventional protein secretion pathway for galectin-3 that is mediated by phase separation and condensation. Using four lysosomal damage models, we observed a rapid, pronounced release of galectin-3 in large, non-exosomal particles. This secretion is driven by glycoprotein-induced galectin-3 phase separation and is independent of pyroptosis and secretory autophagy. During phase separation, the S-face of galectin-3 carbohydrate recognition domain binds glycoproteins that triggers galectin-3 N-terminal tail release and condensation. These condensates then recruit ALG-2 via the exposed N-terminal tail. ALG-2 directs the condensates to the endoplasmic reticulum-late endosome interface. After translocation into late endosomes, galectin-3 condensates are secreted into the extracellular milieu by SNARE-dependent vesicular transport. This mechanism of exporting phase-separated protein condensates may serve as a clean-up response to membrane damage.

DOI: https://doi.org/10.1038/s41467-026-76321-w

Eur Heart J. 2026 Sep 02. pii: ehag606. [Epub ahead of print]

Great debate: diabetic cardiomyopathy is a distinct disease.

Petar Seferovic, Nikolaus Marx, Marija Polovina, Stefano Del Prato, Ovidiu Chioncel, Paul Balfanz, Geneviève Derumeaux, Katharina Marx-Schütt, Johann Bauersachs.

Keywords: Cardiomyopathy; Diabetes; Heart failure; Pharmacotherapy; Prevention

DOI: https://doi.org/10.1093/eurheartj/ehag606

Talanta. 2026 Aug 27. pii: S0039-9140(26)01178-1. [Epub ahead of print]312(Pt B): 130522

DNA nanodevice-mediated perinuclear accumulation of lysosomes for functional regulation.

Weihong Yang, Zhaoyang Wang, Xiangli Li, Dunji Shu, Yao He, Xinran Lian, Shuxin Sun, Xiaowei Feng, Xiaoyan Wu, Cheng Cui, Zhimin Wang, Hui Wu, Liping Qiu, Weihong Tan.

The cellular positioning of lysosomes, especially their perinuclear accumulation, plays an essential role in regulating many biological processes. In this work, we developed a non-genetic approach to drive lysosomes to the perinuclear region by displaying a nucleus-targeting DNA nanodevice on their outer surface. Our experimental results demonstrated that this nanodevice efficiently anchored onto the outer leaflet of lysosomal membrane, and then effectively promoted perinuclear clustering of lysosomes. Further analysis revealed that this repositioning significantly enhanced autophagic flux and altered the expression of autophagy-associated genes. Our study provides a versatile platform for elucidating the functional consequences of lysosomal positioning and its regulatory mechanisms in cellular physiology.

Keywords: Autophagy; DNA nanodevice; Lysosomal distribution; Lysosome; Perinuclear accumulation

DOI: https://doi.org/10.1016/j.talanta.2026.130522