bims-mecosi 2026-07-19 papers

Issue of 2026–07–19
four papers selected by
Verena Kohler, Umeå University

Chem Biol Interact. 2026 Jul 14. pii: S0009-2797(26)00360-1. [Epub ahead of print]437 112252

ER stress promoted MAMs formation and ER-Mito Ca2+ transfer: implication for fluoride-induced hippocampal neuronal injury and cognitive deficits in mice.

Siman Lin, LuYang Cao, Yuzhe Zhou, Shengdan Liu, Yue Yan, Qiwei Zhang, Quan Yuan, Yufei Gao, Ge Du, Jun Hu, Dongmei Wang, Hua Fan.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are crucial contributors to the pathophysiological progression of fluorosis. Recently, the disturbance of the linked membrane microdomains between ER and mitochondria (ER-derived mitochondria-associated membranes, MAMs) has been implicated in fluoride toxicity. Therefore, this study aims to elucidate the involvement of MAMs in fluoride neurotoxicity, specifically by examining how MAMs regulate ER-mitochondria crosstalk and contribute to subsequent hippocampal damage and cognitive dysfunction. In the current investigation, our experimental results observed significant ER stress and aberrant MAMs formation as well as the upregulation of the IP3R1/Grp75/VDAC1 calcium channel proteins in fluoride-treated hippocampal HT-22 neurons and mouse hippocampus. Enhancement of ER-mitochondrial Ca2+ transfer triggered mitochondrial Ca2+ overload, thereby accelerating mtROS production and the dissipation of mitochondrial membrane potential (MMP), leading to Cyt c release-mediated apoptosis in fluoride-treated mouse hippocampal HT-22 neurons. Conversely, uncoupling the IP3R1/Grp75/VDAC1 calcium channel by silencing Grp75 effectively blocked fluoride-induced ER-mitochondrial Ca2+ transfer and mitochondrial Ca2+ overload-mediated hippocampal neuronal apoptosis. Furthermore, ER stress inhibitor 4-phenylbutyric acid (4-PBA) substantially attenuated fluoride-induced enhancement of MAMs formation and IP3R1/Grp75/VDAC1 expression as well as mitochondrial Ca2+ overload-mediated apoptotic hippocampal neuron. Importantly, pretreatment with 4-PBA proved highly effective in reversing fluoride-induced deficits, including neuronal injury, synaptic dysfunction, and cognitive impairment. Collectively, our data suggested a previously unrecognized mechanism underlying fluoride-induced hippocampal neuronal death that ER stress enhanced MAMs formation and ER-mitochondrial Ca2+ transfer via the IP3R1/Grp75/VDAC1 complex and provided a potential therapeutic target for the treatment of fluoride-associated neurotoxicity and neurobehavioral disorders.

Keywords: Apoptosis; Cognitive deficits; ER stress; ER-Mito Ca(2+) transfer; Fluoride; MAMs

DOI: https://doi.org/10.1016/j.cbi.2026.112252

Front Immunol. 2026 ;17 1879836

Calcium imbalance drives organelle network collapse and immune remodeling: novel pathogenic mechanisms in MASLD progression.

Senping Xu, Ziyang Jiang, Qing Zhang, Jiawei Guo.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is initiated by ectopic lipid accumulation, but the precise mechanochemical transducers driving its progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis remain incompletely understood. This review comprehensively elucidates the central pathogenic role of intracellular calcium signaling dysregulation in MASLD. We detail how the metabolically toxic microenvironment induces pathological biophysical remodeling of lipid rafts and key calcium transporters across the plasma membrane (PM), endoplasmic reticulum (ER), and mitochondria. This pervasive transmembrane and inter-organellar calcium imbalance precipitates severe organelle network collapse, characterized by calcium depletion-driven ER stress, mitochondrial dysfunction, and the structural derangement of mitochondria-associated ER membranes (MAMs). Aberrant calcium fluxes function as critical secondary messengers that dictate hepatic immune microenvironment remodeling, at the cellular level driving Kupffer cell pro-inflammatory polarization, NLRP3 inflammasome assembly, and the amplification of damage-associated molecular patterns (DAMPs). These calcium-dependent immune-metabolic feedback loops synergistically trigger hepatic stellate cell (HSC) transdifferentiation and fibrogenesis. Finally, we highlight the latent calcium-regulatory mechanisms of current metabolic therapeutics and prospect the translational potential of targeted calcium modulators coupled with advanced nanodelivery systems, advocating for multi-targeted pharmacological strategies to arrest irreversible liver injury.

Keywords: NLRP3 inflammasome; calcium signaling dysregulation; immune microenvironment remodeling; lipotoxicity; liver fibrosis; metabolic dysfunction-associated steatotic liver disease; mitochondrial dysfunction

DOI: https://doi.org/10.3389/fimmu.2026.1879836

Biochimie. 2026 Jul 17. pii: S0300-9084(26)00167-7. [Epub ahead of print]

ER quality control: how cells detoxify their own membrane from lipid stress.

Helin Elhan, Abdou Rachid Thiam.

The endoplasmic reticulum (ER) is the principal site of glycerolipid synthesis in eukaryotic cells. The continuous production of lipid intermediates, including phosphatidic acid (PA), diacylglycerol (DAG), and triacylglycerol (TAG), destabilizes the ER membrane when they accumulate. To maintain bilayer integrity, cells deploy two sequential strategies: enzymatic conversion of these intermediates into membrane-compatible phospholipids, and their physical sequestration into lipid droplets (LDs), ER-derived organelles whose biogenesis is actively regulated by the seipin complex. LD growth is further sustained by the relocalization of TAG-synthesizing enzymes to the LD surface and by bridge-like lipid transfer proteins at ER-LD contact sites. When these mechanisms are overwhelmed, the accumulation of non-bilayer lipids drives ER stress and lipotoxicity, thereby contributing to the development of metabolic diseases. Here, we review the molecular logic of ER lipid quality control, from intermediate-driven membrane stress to the regulated responses that neutralize it.

Keywords: Diacylglycerol; Kennedy pathway; endoplasmic reticulum; ferroptosis; lipid droplets; lipid quality control; lipotoxicity

DOI: https://doi.org/10.1016/j.biochi.2026.07.007

Plant J. 2026 Jul;127(1): e71038

Functional analysis of LIPID TRANSFER PROTEIN 6 (LTP6) in pennycress and Arabidopsis reveals divergent roles in oil storage and seed coat development.

Athanas Guzha, Julius Ver Sagun, Christopher Johnston, Payton Whitehead, Ana Paula Alonso, Kent D Chapman.

In angiosperms, lipid transfer proteins (LTPs) perform multiple roles, including the shuttling of lipids between organelles and to/through the apoplast. In pennycress (Thlaspi arvense L.), the LIPID TRANSFER PROTEIN 6 (TaLTP6) was identified as highly expressed in developing embryos, especially in high-oil accessions. Ectopic expression of pennycress LTP6 (TaLTP6) in Nicotiana benthamiana and Arabidopsis thaliana leaf mesophyll cells induced the proliferation of cytoplasmic lipid droplets (LDs), suggesting a role in neutral lipid accumulation. GFP-tagged TaLTP6 localized predominantly to LDs and endoplasmic reticulum (ER)/LD contact sites, while its Arabidopsis homolog, AtLTP6, localized to the ER and apoplast. Domain-swapping experiments revealed that their N-terminal regions determined these subcellular localizations. Loss-of-function mutants of Arabidopsis ltp6 exhibited major disruptions in LD organization in mature embryos, characterized by large lipid aggregates, and reduced seed oil content. Proteomics analysis revealed mislocalization of LD- and ER-associated proteins in ltp6 mutants, suggesting impaired LD biogenesis. Further, Arabidopsis ltp6 seeds exhibited reduced mucilage extrusion and impaired germination, pointing to a secondary role for AtLTP6 in seed coat function. Complementation of Arabidopsis ltp6 with TaLTP6 restored LD morphology and seed oil levels, but did not rescue mucilage and germination defects, indicating functional divergence between the two homologs. We conclude that LTP6 plays a dual role in seeds: (1) participation in embryo lipid storage, and (2) contribution to seed coat integrity and germination. The embryo-specific expression of TaLTP6 in pennycress suggests that it retained its evolutionary role in lipid storage, but lost functions related to seed coat development and germination.

Keywords: embryos; endoplasmic reticulum; lipid droplets; mucilage; pennycress; seed coat; seed germination

DOI: https://doi.org/10.1111/tpj.71038