bims-mecosi 2026-08-09 papers

Issue of 2026–08–09
four papers selected by
Verena Kohler, Umeå University

Front Endocrinol (Lausanne). 2026 ;17 1852671

Long-chain saturated free fatty acids induce pancreatic β-cell lipotoxic stress via H2O2-mediated mitochondria-associated membrane remodeling.

Sarah Sharifi, Meike Knittel, Maren Böger, Anne Jörns, Ilir Mehmeti.

Introduction: Type 2 diabetes (T2D) is characterized by progressive pancreatic β-cell dysfunction and loss, driven by chronic exposure to elevated circulating free fatty acids (FFAs). Mitochondria-associated endoplasmic reticulum membranes (MAMs), the specialized contact sites between the endoplasmic reticulum (ER) and mitochondria, regulate cellular metabolism and survival, yet their role in β-cell lipotoxicity remains unclear.
Methods: We examined the impact of physiologically relevant long-chain saturated (palmitic and stearic acid) and unsaturated (palmitoleic and oleic acid) FFAs, applied alone or in combination, on MAM formation in insulin-secreting INS-1E cells. ER-mitochondria contacts were quantified by proximity-ligand assay (PLA), transmission electron microscopy and genetically encoded MAM sensors. The role of reactive oxygen species was investigated using the H2O2-scavenging enzyme glutathione peroxidase 8 (GPX8). To test causality, ER-mitochondria coupling was artificially enhanced with a synthetic ER-mitochondrial linker.
Results: Saturated FFAs significantly increased ER-mitochondria contacts, whereas unsaturated FFAs had no negative effect and counteracted the saturated FFA-induced MAM formation. Expression of GPx8 suppressed palmitate-induced MAM formation, indicating that H2O2-mediated oxidative stress is required for the saturated FFA-induced MAM remodeling. Cells expressing the synthetic linker displayed heightened susceptibility to lipotoxic stress, confirming that sustained ER-mitochondria coupling promotes β-cell death.
Conclusions: Our data demonstrate that dysregulated MAMs constitute a mechanistic link between saturated-FFA-induced lipotoxic stress and β-cell failure in T2D. Targeting MAM remodeling or the upstream H2O2 signal may represent a novel therapeutic avenue to preserve β-cell function under lipotoxic conditions.

Keywords: ER-mitochondria coupling; H2O2; MAM formation; lipotoxicity; type 2 diabetes; β-cell failure

DOI: https://doi.org/10.3389/fendo.2026.1852671

Life Sci. 2026 Aug 07. pii: S0024-3205(26)00433-9. [Epub ahead of print] 124624

Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.

Yiqin Yan, Lupeng Chen.

Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.

Keywords: Adipose tissue; Lipid droplets; Lipophagy; Metabolic disease; Mitochondria; Organelle contact sites; Peroxisomes

DOI: https://doi.org/10.1016/j.lfs.2026.124624

Mol Cell Endocrinol. 2026 Aug 03. pii: S0303-7207(26)00157-7. [Epub ahead of print] 112880

IP3R drives cardiomyocyte injury by enhancing MAM-mediated Ca2+ transfer and mitochondrial dysfunction.

Haihui Yang, Jinming Zhu, Guifang Li, Ranran Li, Ankang Peng, Hang Zhang.

BACKGROUND: Heart failure (HF) is the terminal stage of various cardiovascular diseases. Mitochondrial Ca2+ overload and dysfunction mediated by mitochondria-associated ER membranes (MAMs) are recognized contributors to HF pathogenesis; however, the underlying molecular mechanisms remain incompletely understood.
METHODS: An in vitro model of cardiomyocyte injury was established using angiotensin II (Ang II)-stimulated H9c2 cells. IP3R was knocked down using specific siRNA. Cell viability (CCK-8), apoptosis (Annexin V/TUNEL), and hypertrophy (phalloidin staining) were assessed. IP3R expression and mitochondrial complex subunits were analyzed by western blotting. MAM formation was examined by transmission electron microscopy and immunofluorescence co-localization. Mitochondrial function was evaluated by measuring ATP levels, ROS (MitoSOX), mitochondrial membrane potential (TMRM), and Ca2+ uptake (Rhod-2).
RESULTS: Ang II stimulation reduced cell viability, induced hypertrophy and apoptosis, and promoted MAM formation. Mechanistically, Ang II upregulated IP3R expression and enhanced MAM-mediated mitochondrial Ca2+ overload, leading to decreased mitochondrial membrane potential, elevated ROS, and reduced ATP production. Notably, genetic knockdown of IP3R attenuated these pathological changes, reducing MAM formation and mitochondrial Ca2+ overload while restoring mitochondrial function and cell viability.
CONCLUSION: Our findings suggest that IP3R may exacerbate cardiomyocyte injury by facilitating MAM-mediated Ca2+ transfer and mitochondrial dysfunction, indicating that targeting IP3R could represent a potential therapeutic strategy for HF. However, the upstream mechanisms of IP3R upregulation and the causal role of mitochondrial Ca2+ uptake require further investigation.

Keywords: Heart failure; IP3R; MAM (mitochondrial-associated endoplasmic reticulum membrane); mitochondrial Ca(2+); mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.mce.2026.112880

PLoS Pathog. 2026 Aug;22(8): e1014473

The parasitophorous vacuole membrane of Toxoplasma gondii: A custom structural framing with smart interior plumbing for resource allocation.

Julia D Romano, Shahbaz M Khan, Isabelle Coppens.

In essence, the parasitophorous vacuole (PV) of Toxoplasma is a "Do-It-Yourself" renovation project led by the parasite after invasion of a guest house (the host cell) to install itself surreptitiously in a private and custom-built room, reinforced by drywall (the PV membrane). The function of the PV membrane (PVM) is to keep away the host security guards (immune response, lysosomes) from the parasite while allowing necessary and controlled access to host resources. Inside the PV, Toxoplasma relies on a crew of creative interior designers (the GRA proteins or GRA) to remodel and transform the space into an efficient living and breeding suite. Some GRA set up specialized delivery systems in the PVM (pores) to siphon off groceries (nutrients) from the host cytosol. Other GRA build a complex network of tubules that attach to the PVM (intravacuolar network) to trap large grocery stores (host organelles) inside the PV, ensuring the massive supply of selective food (lipids). In a parallel circuit, specific GRA recruit host proteins at the PVM that shape this membrane and mediate scission (host ESCRT) to engulf more host resources. In addition to this interior layout, Toxoplasma establishes a plumbing system made of PVM tubules that pervade the host cell, which maximizes the surface area for nutrient uptake, and lasso host organelles (lipid droplets, ER) from the surroundings. Finally, the PV acts as a magnet to attract and keep possession of some host organelles (mitochondria, the ER) by hijacking their molecular Velcro (Membrane Contact Sites), allowing the parasite to tap into the host power grid to fuel its own metabolic needs.

DOI: https://doi.org/10.1371/journal.ppat.1014473