bims-mecosi 2025-06-22 papers

Issue of 2025–06–22
six papers selected by
Verena Kohler, Umeå University

Front Endocrinol (Lausanne). 2025 ;16 1573499

Endoplasmic reticulum-mitochondria crosstalk: new mechanisms in the development of atherosclerosis.

Mingxiao Li, Yili Xiao, Ling Dai, Simin Chen, Wanjuan Pei, Chao Tan.

Atherosclerosis (AS) is a global public health concern and involves a complex pathogenesis characterized by lipid abnormalities, oxidative stress, and inflammatory responses at the cellular and molecular levels. The crosstalk between the endoplasmic reticulum (ER) and mitochondria, mediated by mitochondria-associated membranes (MAMs), plays a critical role in the pathogenesis of atherosclerosis. As two key cellular organelles, the ER and mitochondria interact physically and functionally through MAMs, which serve as bridges between their close contact and interdependence. MAMs maintain lipid homeostasis, promote calcium ion transport, the oxidative stress response, apoptosis, and autophagy. Recent studies have highlighted the significance of ER-mitochondria crosstalk in the progression of AS, as indicated by mitochondrial and ER structural and functional integrity, redox homeostasis, and calcium homeostasis. This review comprehensively explores the novel mechanisms of ER-mitochondria crosstalk in AS and emphasizes the potential of MAMs as therapeutic targets, aiming to provide new perspectives and strategies for the treatment of cardiovascular diseases.

Keywords: atherosclerosis; endoplasmic reticulum; endoplasmic reticulum contact complex; endoplasmic reticulum-mitochondrial crosstalk; mitochondria; mitochondria-associated membranes (MAMs)

DOI: https://doi.org/10.3389/fendo.2025.1573499

Front Cardiovasc Med. 2025 ;12 1535401

The structure and function of mitofusin 2 and its role in cardiovascular disease through mediating mitochondria-associated endoplasmic reticulum membranes.

Yuhu Lv, Liyuan Chen, Long Li, Ziyuan Liao, Zuoming Fang, Lin Cheng, Fenglin Peng.

Cardiovascular disease (CVD) remains a leading cause of death globally, posing a major public health challenge. Due to the complexity of CVD's etiology, understanding its pathogenesis has been a significant challenge and research focus. In recent years, the communication between organelles has gained increasing attention, with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) emerging as a key structural component that facilitates dialogue between the mitochondria and the ER. Numerous studies have highlighted that proteins located in MAMs may play a role in the development of CVD. Among these, mitofusin 2 (MFN2), a protein found on the outer mitochondrial and ER membranes, has garnered particular interest due to its widespread presence in MAMs. This review aims to sort out current research on MFN2, focusing on its potential involvement in myocardial protection through its mediation of MAMs. We discuss how MFN2-mediated MAMs may contribute to the protection against various CVDs, including myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, dilated cardiomyopathy, pathological myocardial hypertrophy, cardiotoxicity, and heart failure. However, given the functional diversity of MFN2, the current body of research remains controversial, and further studies are urgently needed to clarify its precise mechanisms of action.

Keywords: cardioprotection; cardiovascular disease; endoplasmic reticulum; mitochondria; mitochondria-associated endoplasmic reticulum membranes; mitofusin 2

DOI: https://doi.org/10.3389/fcvm.2025.1535401

Nat Cell Biol. 2025 Jun;27(6): 902-917

Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.

Maria Livia Sassano, Yulia Y Tyurina, Antigoni Diometzidou, Ellen Vervoort, Vladimir A Tyurin, Sanket More, Rita La Rovere, Francesca Giordano, Geert Bultynck, Benjamin Pavie, Johan V Swinnen, Hülya Bayir, Valerian E Kagan, Luca Scorrano, Patrizia Agostinis.

The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.

DOI: https://doi.org/10.1038/s41556-025-01668-z

Phytomedicine. 2025 Aug;pii: S0944-7113(25)00590-2. [Epub ahead of print]144 156952

Dendrobine attenuates lipopolysaccharide-induced acute lung injury by modulating FAM134B-mediated endoplasmic reticulum autophagy and mitochondrial function.

Jia Zhou, Sanzhong Li, Zhiguo Hu, Shuying Huang, Yuting Yang, Chaoqi Zhou, Shichao Zhang, Kaihang Luo, Cheng Wang, Cheng Qing, Zhenguo Zeng.

BACKGROUND: Macrophage-mediated excessive inflammatory responses play a pivotal role in sepsis progression, particularly in the lungs. Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, also contribute to the development of acute lung injury (ALI). Dendrobine is a natural alkaloid known to alleviate ERS in various diseases; however, its specific role in sepsis-associated ALI is not yet fully understood.
OBJECTIVE: This study investigates the protective effects of dendrobine against ALI and elucidates the underlying mechanisms.
METHODS: We assessed the protective effects of dendrobine using LPS-induced THP-1 cells and a murine model of sepsis. Techniques included HE staining for lung tissue damage, TUNEL staining for pulmonary apoptosis, flow cytometry for intracellular reactive oxygen species (ROS) levels and apoptosis, transmission electron microscopy for ER autophagy and changes in mitochondria-associated ER membranes (MAMs), and confocal microscopy for ER autophagy flux, mitochondrial membrane potential, and mitochondrial calcium ion levels.
RESULTS: Dendrobine significantly alleviated LPS-induced ALI and inflammatory responses in mice by reducing the expression of ERS-related and pro-apoptotic proteins. It enhanced ER autophagy by upregulating FAM134B, inhibiting its ubiquitination and degradation, and promoting its interaction with LC3B. Dendrobine partially restored LPS-induced mitochondrial dysfunction by reducing MAM formation. Conversely, FAM134B knockdown reversed the protective effects of dendrobine.
CONCLUSION: This study demonstrates that dendrobine alleviates LPS-induced ERS and mitochondrial dysfunction through FAM134B-mediated ER autophagy and MAM reduction, thereby protecting lung tissue. These findings highlight the potential of dendrobine as a therapeutic agent against sepsis-induced ALI.

Keywords: Dendrobine; Endoplasmic reticulum autophagy; Endoplasmic reticulum stresses; FAM134B; Mitochondria-associated endoplasmic reticulum membranes; Septic lung injuries

DOI: https://doi.org/10.1016/j.phymed.2025.156952

J Ethnopharmacol. 2025 Jun 13. pii: S0378-8741(25)00835-9. [Epub ahead of print] 120147

Harpagide from Radix Scrophulariae Attenuated Ischemic Stroke Injury Through Calcium Homeostasis Regulation Between Mitochondria-Associated Membranes via the IP3R1/GRP75/VDAC1 Complex.

Ke Wang, Yue Wang, Huai-Yu Liu, Geng-Zheng Su, Yuan-Yuan Dong, Yue Chen, Yan-Ping Wang, Zhi He.

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous studies have provided evidence supporting the significant roles of Radix Scrophulariae in the treatment of fevers, bacterial infection and encephalopathy. In particular, harpagide, a prominent iridoid glycosides derived from Radix Scrophulariae, the representative component of Radix Scrophulariae, has demonstrated noteworthy neuroprotective against cerebral ischemic injury. However, the precise mechanisms that underlie its anti-ischemic effects remain unclear.
PURPOSE: The aim of this study is to elucidate the in vitro and in vivo neuroprotective effects of harpagide and the mechanisms involved in mitochondria-associated membranes (MAMs).
METHODS AND MATERIALS: The neuroprotective effects of harpagide were evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining and the Longa Neurological Function Score in vivo. JC-1, fluorescein diacetate (FDA)/propidium iodide (PI) staining, a western blot assay, and RT-PCR were used to assess the mitochondria-associated neuroprotective impacts of harpagide on primary cortical neurons. The harpagide effects on the endoplasmic reticulum (ER), mitochondrial calcium ion concentrations, and double immunofluorescence was used to assess the harpagide effects on the expression and co-localization of the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)/glucose-regulated protein 75 (GRP75)/voltage-dependent anion channel 1 (VDAC1) complex in the MAMs of neurons. Additionally, RT-PCR and a western blot assay were used to quantify these protein expression levels on primary cortical neurons. Furthermore, MAMs were evaluated using specific calcium ion fluorescent probes and immunofluorescence both in vivo and in vitro.
RESULTS: Harpagide mitigated cerebral injury in the MCAO model. In addition, neuronal mitochondrial damage and mitochondria-mediated apoptosis factors in the OGD model significantly decreased by harpagide. Harpagide also significantly ameliorated the neuronal calcium homeostasis imbalance and mitigated MAM alterations in both the MCAO and OGD models. Harpagide also reduced the co-localization and expressions of inositol IP3R1, GRP75, and the VDAC1 in the OGD model.
CONCLUSION: This study provided evidence that harpagide regulated calcium homeostasis within MAMs via the IP3R1/GRP75/VDAC1 complex, thereby reducing mitochondria-mediated neuronal apoptosis and alleviating IS injury both in vivo and in vitro. These findings offer a novel research direction for the therapeutic application of harpagide in ischemic stroke (IS).

Keywords: Calcium Homeostasis; Harpagide; IP(3)R1/GRP75/VDAC1; Ischemic Stroke; MAMs

DOI: https://doi.org/10.1016/j.jep.2025.120147

Front Pharmacol. 2025 ;16 1509317

Congrong Shujing Granules ameliorates mitochondrial associated membranes to against MPP+-induced neurological damage in the cellular model of Parkinson's disease.

Chutian Zhang, Peizhen Huang, Huiling Cheng, Xinxin Yuan, Mei Zhou, Ying Liu, Ting Liu, Dan Chen, Qian Xu, Jing Cai.

Context: Congrong-Shujing Granules (CRSJG) are known to protect dopaminergic neurons in Parkinson's disease (PD), and the mechanism may be related to the improvement of mitochondria-associated membranes (MAMs).
Objective: To investigate the impact of CRSJG-medicated serum on MAMs in the 1-methyl-4-phenylpyridinium (MPP+)-induced PD cell model.
Materials and methods: Human neuroblastoma (SH-SY5Y) cells were treated with 1,000 μmol/L MPP+ for 24 h, resulting in three experimental groups: MPP+, CRSJG, and 2-APB. The MPP+ group received blank serum, CRSJG group was treated with CRSJG-medicated serum, and the 2-APB group was given 100 μmol/L 2-APB. An untreated control group was also included. Serum pharmacokinetics for the CRSJG group were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. Intracellular-Ca2+, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis rates were measured using fluorescent probes and flow cytometry. Transmission electron microscopy was employed to examine the morphology of MAMs. Western blot was conducted to identify proteins related to apoptosis and Ca2+ transport.
Results: CRSJG-medicated serum identified by pharmacokinetic markers including echinacoside, paeoniflorin, salvianolic acid B, acteoside, and tanshinone IIa. The EC50 for MPP+-induced reduction in cell proliferation was 1,110 μmol/L. CRSJG-medicated serum, especially at 2.5%, significantly improved cell proliferation after 24 h. The serum effectively mitigated damage within the MAMs region and reduced both the mitochondrial-Ca2+ fluorescence intensity and the expression of the IP3R-VDAC-MCU complex in MPP+-induced neuronal cells. Additionally, it significantly decreased the levels of ROS, the decline in MMP, and apoptosis rates in these cells.
Discussion and conclusion: The findings provide novel insights into the potential of CRSJG in treating neuronal loss in PD.

Keywords: IP3R-VDAC-MCU complex; mitochondrial calcium overload; nerve cell apoptosis; neuroprotection; reactive oxygen species

DOI: https://doi.org/10.3389/fphar.2025.1509317