bims-mecosi 2025-12-07 papers

Issue of 2025–12–07
seven papers selected by
Verena Kohler, Umeå University

Int J Mol Med. 2026 Feb;pii: 34. [Epub ahead of print]57(2):

Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review).

Yan Wang, Baowei Feng, Yanting Wu, Zongle Sun, Hao Yuan, Wei Chen, Chang Zhao, Zhi Liu.

Ischemic heart disease remains the leading cause of global disease burden among cardiovascular disorders. In addition to cardiomyocyte injury, ischemia-reperfusion (I/R)-induced microvascular damage plays a crucial role in determining tissue dysfunction and overall prognosis. Mitochondria-associated endoplasmic reticulum membranes (MAMs), specialized contact sites between the ER and mitochondria, are now recognized as key regulators of cardiovascular pathophysiology. The present review summarized current knowledge of the structure of MAMs and their effects on endothelial cells under hypoxia/reoxygenation conditions. Particular attention was given to their role in regulating mitochondrial quality control processes, including fission, fusion, oxidative stress, mitophagy and Ca2+ homeostasis, within the context of cardiac microvascular I/R injury. Targeting MAMs may represent a promising strategy for microvascular protection in ischemic heart disease.

Keywords: Ca2+ homeostasis; mROS; microvascular I/R injury; mitochondria-associated membranes; mitochondrial dynamics

DOI: https://doi.org/10.3892/ijmm.2025.5705

J Ethnopharmacol. 2025 Nov 27. pii: S0378-8741(25)01650-2. [Epub ahead of print]358 120958

Mechanism of Shenzhu components in alleviating chemotherapy-induced diarrhea via mitochondria-associated endoplasmic reticulum membranes (MAMs) regulation.

Zhangjing Cao, Ruizhi Liu, Kedi Li, Jiayao Sun, Xinya Wen, Fei Tang, Lin Liu, Fu Peng, Cheng Peng, Hui Ao.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemotherapy-induced diarrhea (CID) is a common side effect of 5-fluorouracil (5-FU). Traditional Chinese medicine (TCM) is responsible for the core pathogenesis of spleen qi deficiencies. Therefore, the herbal pair of the rhizomes of Atractylodes macrocephala Koidz. (AM) and the roots of Panax ginseng C. A. Mey. (PG) known for its effects on tonifying qi and strengthening the spleen, has been traditionally used to improve gastrointestinal function.
AIM OF THE STUDY: This study aimed to elucidate how the combination of Atractylodis Macrocephalae volatile oil (AMO) and Panax ginseng total saponins (PGS) (AP) regulated mitochondria-associated endoplasmic reticulum membranes (MAMs) to restore intestinal barrier function in CID.
METHODS: A 5-FU-induced CID mouse model was used to evaluate the effects of AP on diarrhea scores and body weight. Hematoxylin-eosin (HE) staining was used to examine colon pathological changes. Transmission electron microscopy (TEM) was used to observe MAMs, endoplasmic reticulum (ER), and mitochondrial ultrastructure. Immunohistochemistry was performed to detect ER stress markers (CHOP and GRP78) and biochemical assays were used to assess mitochondrial function (membrane potential, ROS, and ATP). The TUNEL assay was conducted to measure cell apoptosis. RNA sequencing (RNA-seq) and bioinformatics analysis were combined to explore the underlying mechanisms, followed by validation of related proteins (cGMP, PKG, IP3R, GRP75, VDAC1, MCU, Mfn2, ZO-1, Occludin, Bcl-2 and Bax) using ELISA, Western blotting(WB), and immunofluorescence.
RESULTS: AP significantly alleviated 5-FU-induced body weight loss, diarrhea, and colonic pathological damage in mice, while restoring intestinal barrier permeability markers. TEM revealed that AP reversed 5-FU-induced mitochondrial swelling, cristae loss, and ER dilation and fragmentation. Further studies demonstrated that 5-FU disrupted MAMs homeostasis, whereas AP restored the normal MAMs structure by downregulating Mfn2 expression. At the mechanistic level, RNA-seq analysis demonstrated that AP alleviated CID by coordinating the regulation of multiple factors, including mitochondrial function and endoplasmic reticulum homeostasis, with activation of the cGMP-PKG signaling pathway identified as a central therapeutic mechanism, which was verified by WB. AP activated the cGMP-PKG pathway to suppress IP3R-mediated ER calcium release and downregulated the MAMs calcium channel complex (IP3R-GRP75-VDAC1-MCU), thereby ameliorating mitochondrial dysfunction and ER stress while reducing mitochondrial calcium overload. Ultimately, AP inhibited apoptosis by modulating the Bcl-2/Bax balance and restored intestinal barrier integrity through the upregulation of tight junction proteins.
CONCLUSION: This study revealed for the first time that 5-FU induced intestinal barrier damage by disrupting the structure and function of MAMs. In contrast, AP corrected calcium imbalance and contacted abnormality through the cGMP-PKG-MAMs axis, resulting in multidimensional relief of CID. This finding provided a novel therapeutic target (MAMs) for CID and highlighted the unique advantage of Chinese herbal complexes in modulating organelle interactions.

Keywords: 5-FU; Atractylodes macrocephala volatile oil; Chemotherapy-induced diarrhea; Endoplasmic reticulum; MAMs; Mitochondria; Panax ginseng total saponins

DOI: https://doi.org/10.1016/j.jep.2025.120958

Biomed Pharmacother. 2025 Nov 29. pii: S0753-3322(25)01029-7. [Epub ahead of print]193 118835

Endoplasmic reticulum, mitochondria, and their crosstalk in retinal ganglion cell degeneration.

Baohua Li, Yipeng Shi, Mengyu Liu, Wengxuan Cao, Fuyuan Zhang, Zefeng Kang.

Retinal ganglion cells (RGCs) serve as the terminal output neurons in the retina and are responsible for transmitting visual information from photoreceptors to higher-level centers in the brain. Because of their highly polarized structure, substantial energy demands, and complex protein synthesis activities, the function of RGCs is critically dependent on the homeostasis of intracellular organelles, particularly the endoplasmic reticulum (ER) and mitochondria. Recent studies have shown that these two organelles engage in close physical and functional crosstalk through specific microdomains known as "mitochondria-associated ER membranes" (MAMs), which are crucial for the survival and function of RGCs. This review delves into the critical roles of the ER and mitochondria in the mechanisms of RGC degeneration. Furthermore, the mechanisms by which mitochondrial-ER contact site (MERC)-mediated interorganelle communication exacerbates RGC degeneration by disrupting Ca2 + homeostasis and inducing ER stress and oxidative stress are elucidated. Drugs targeting mitochondria, ER, and MERCs to prevent and treat RGC degeneration are summarized to provide new perspectives and references for studying the pathological mechanisms of RGC degeneration and developing targeted therapeutic strategies.

Keywords: Endoplasmic reticulum; Mitochondria; Mitochondria-associated membrane; Retinal ganglion cell; Retinal neuron degeneration

DOI: https://doi.org/10.1016/j.biopha.2025.118835

Mol Biomed. 2025 Dec 02. 6(1): 129

Cholesterol induced-mitochondrial calcium dysregulation facilitates atherosclerosis by promoting lipid accumulation in vascular smooth muscle cells.

Zhiwang Zhang, Fan Yang, Wei Wang, Qi Cao, Long Zhang, Yu Zhang, Dong Ma, Xinhua Zhang, Jinkun Wen, Bin Zheng.

Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis.

Keywords: Atherosclerosis; MCU inhibitor; MICU1; Mitochondrial calcium

DOI: https://doi.org/10.1186/s43556-025-00384-2

EMBO J. 2025 Dec 02.

E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival.

Luyi Jiang, Jiangfen Tang, Ya-Fen Zhang, Wen-Xuan Zou, Gang Deng, Na Tian, Xiaolu Zhao, Lei Han, Kai Liu, Bao-Liang Song, Jie Luo.

Localization of lysosomes influences their properties, e.g., perinuclear lysosomes are more acidic but less mobile compared with the peripheral ones. Furthermore, the endoplasmic reticulum (ER) can actively regulate the dynamics and functions of lysosomes via membrane contact sites. In this study, we find that ER-resident apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1) establishes membrane contacts with lysosomes by directly interacting with the Voa subunit of V-ATPase. AREL1 also catalyzes K33-linked polyubiquitylation of V-ATPase V1B2 subunit, inducing its binding to UBAC2 localized in the perinuclear ER. Depletion of AREL1 or UBAC2 increases the number of peripheral lysosomes that possess partially assembled V-ATPase, elevated luminal pH, and attenuated degradative capacity. Knockdown of ZRANB1, the deubiquitylating enzyme that antagonizes AREL1-mediated V1B2 ubiquitylation, promotes perinuclear clustering of lysosomes and increases lysosomal acidity and degradation. Mice lacking Arel1 exhibit age-dependent Purkinje cell loss, an ataxic phenotype, and motor impairment. Lipofuscin accumulation in the residual Purkinje cells of Arel1-/- mice indicates lysosomal dysfunction. Orchestration of lysosomal positioning and function by the AREL1-UBAC2-V-ATPase axis underscores the physiological significance of ER-regulated perinuclear lysosomal positioning in neurons.

Keywords: AREL1; Lysosomal Positioning; Purkinje Neurons; UBAC2; V-ATPase

DOI: https://doi.org/10.1038/s44318-025-00654-3

Br J Pharmacol. 2025 Dec 02.

Molecular glue neferine induces BAP31 homodimerisation to disrupt endoplasmic reticulum-mitochondria crosstalk for anti-neuroinflammation in ischaemic stroke.

Ya-Xuan Zhu, Zhuo Yang, Ling Li, Ze-Kun Chen, Fang-Fang Zhuo, Yu-Hui Wang, Zheng-Ping Liu, Bo Han, Wei Yu, Peng-Fei Tu, Tian-Tian Wei, Hua Wang, Ke-Wu Zeng.

BACKGROUND AND PURPOSE: B-cell receptor-associated protein 31 (BAP31), an endoplasmic reticulum (ER)-resident transmembrane protein, has emerged as a critical regulator of immune cell activation, yet its role in neuroinflammation remains unexplored. Here, we uncovered the natural compound neferine (Nef) as a pharmacological modulator of BAP31 that suppressed microglial activation.
EXPERIMENTAL APPROACH: Using thermal protein profiling (TPP), we identified BAP31 as the primary target of Nef. Biochemical and structural analyses were employed to characterise Nef-BAP31 interactions. We evaluated ER stress and mitochondrial energy metabolism homeostasis using techniques such as STER super-resolution technology, flow cytometry, western blot, etc. In vivo validation utilised two models: lipopolysaccharide (LPS)-induced endotoxaemia and middle cerebral artery occlusion (MCAO) for ischaemic stroke, combining behavioural tests, cytokine profiling and histopathological assessments.
KEY RESULTS: Nef functioned as a 'molecular glue' by binding to BAP31's coiled-coil CC2 domain to induce stable dimerisation. We revealed that dimerised BAP31 triggered ER membrane remodelling, which disrupted ER-mitochondria contact sites and preserved mitochondrial energy metabolism homeostasis, thereby blocking inflammatory cytokine release. In vivo, Nef attenuated neuroinflammation in endotoxaemia mice and further conferred neuroprotection against ischaemic stroke in a MCAO model by inhibiting microglia-driven neuronal injury.
CONCLUSIONS AND IMPLICATIONS: In summary, our work reveals that BAP31 is a master regulator of ER-mitochondria communication during microglial activation and introduces a paradigm-shifting 'molecular glue' strategy for targeting ER-resident proteins. Additionally, these findings redefine the pharmacological landscape for modulating organelle interactions in microglia involved in neuroinflammatory diseases.

Keywords: B cell receptor‐associated protein 31 (BAP31); endoplasmic reticulum (ER); ischaemic stroke; microglial polarization; neferine (Nef); neuroinflammation

DOI: https://doi.org/10.1111/bph.70277

Mol Neurobiol. 2025 Dec 05. 63(1): 256

Metformin Ameliorates Early Brain Injury After Subarachnoid Hemorrhage Via Improving Endoplasmic Reticulum Stress and Mitochondrial Stress-Mediated Ca2+ Imbalance.

Zhonghua Zhang, Jingbei Zhang, Liping Li, Lin Zong.

Subarachnoid hemorrhage (SAH) is a destructive subtype of stroke characterized by a high mortality and morbidity rate (45-50%) and a poor neurologic prognosis, encompassing both neurological and psychiatric impairments. It will be more imperative to explore new therapeutic strategies for early brain injury (EBI) to enhance the prognosis of patients with SAH. First, we investigated the role of endoplasmic reticulum stress (ERS) and mitochondrial stress (MS) in mediating the IP3R1-GRP75-VDAC1 Ca2⁺ channeling complex within the first 72 h following SAH in mice. Neurological function was assessed prior to euthanasia, and brain water content was measured post-sacrifice in each group. The ultrastructural composition of mitochondria-associated membrane (MAM) was examined using transmission electron microscopy (TEM). Protein expressions related to ERS, MS, and apoptosis were evaluated by immunofluorescence and Western blot. Metformin (Met) administration improved neurological scores and reduced brain edema at 24 h post-SAH, likely through ameliorating ERS- and MS-mediated Ca2⁺ dysregulation. Finally, the beneficial effect of Met was further confirmed in an in vitro SAH model, yielding consistent results. Stimulation of arterial blood aggravates the ERS and MS through the PTP1B/AKT axis, further affecting the structure and function of the MAM following SAH. The MAM formation mediates the IP3R1-GRP75-VDAC1 complex, playing an important role in Ca2+ transport. The Met treatment could ameliorate ER stress, MS, and Ca2+ overload, further alleviating the EBI of SAH.

Keywords: Apoptosis; Ca2+ ; Early brain injury; Metformin; Subarachnoid hemorrhage

DOI: https://doi.org/10.1007/s12035-025-05558-1