FASEB JOURNAL
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2025
·Vol. 39
·期 18
·e71060
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IF 4.2
Hongyu Liu,Yali Deng,Mei Peng,Yanting Nie,Jingfei Chen
The pathogenesis of preeclampsia (PE) involves endoplasmic reticulum stress (ERS) and the subsequent induction of mitophagy. Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) is a key factor regulating mitophagy, but its role in PE has not been reported. In this study, we aimed to analyze the role of ARIH1 in the pathogenesis of PE. The role of ARIH1 in the pathogenesis of PE was investigated in a PE rat model and in an in vitro hypoxia/reoxygenation (H/R) model using HTR8 trophoblast cells. The study revealed that ARIH1 was upregulated while Mitochondrial fusion protein 2 (MFN2) was downregulated in PE rats and H/R-treated HTR8 cells. Inhibition of ARIH1 reversed the suppressed proliferation and invasion capacities of HTR8 cells under H/R conditions, reduced intracellular reactive oxygen species (ROS) and calcium ions (Ca 2+ ), and modulated the protein expression of LC3II/LC3I, p62, glucose-regulatory protein 78 (GRP78), and C/EBP homologous protein (CHOP). Additionally, mitochondrial membrane potential was improved. Interestingly, treatment with Tunicamycin or Thapsigargin could reverse the inhibitory effects of ARIH1 downregulation on trophoblastic cells by activating endoplasmic reticulum stress (ERS) and mitophagy. Notably, the study identified for the first time that ARIH1 mediates the ubiquitination degradation of MFN2. Inhibition of MFN2 abolished the regulatory effects of ARIH1 downegulation on ERS and mitophagy in trophoblast cells, as well as the associated damage in PE rats. Overall, the findings underscore the crucial role of ARIH1 in regulating mitophagy and ERS through MFN2, highlighting its significance in the pathogenesis of PE. Graphical The mechanism by which ubiquitin ligase ARIH1 promotes the occurrence of preeclampsia through MFN2. Our research found that ARIH1 is an important factor mediating the occurrence and development of PE, as well as mitochondrial autophagy and endoplasmic reticulum stress, and this effect is achieved through MFN2. Mechanistically, it was discovered for the first time that ARIH1 mediated the ubiquitination and degradation of MFN2.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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病理生理学
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围产医学
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信号转导
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DOI
PubMed
高影响因子
Current Medical Science
·
2024
·Vol. 44
·期 5
·964-970
·
IF 2
Xu Mei-xia,Xu Tao,An Ning
Objective Acute respiratory distress syndrome (ARDS) patients currently have relatively high mortality, which is associated with early lung fibrosis. This study aimed to investigate whether miR-17 suppression could alleviate ARDS-associated lung fibrosis by regulating Mfn2. Methods A mouse model of ARDS-related lung fibrosis was constructed via intratracheal instillation of bleomycin. The expression level of miR-17 in lung tissues was detected via quantitative real time polymerase chain reaction (qRT-PCR). In the ARDS mouse model of lung fibrosis, the mitigating effects of miR-17 interference were evaluated via tail vein injection of the miR negative control or the miR-17 antagomir. The pathological changes in the lung tissue were examined via HE staining and Masson’s trichrome staining, and the underlying molecular mechanism was investigated via ELISA, qRT-PCR and Western blotting. Results Bleomycin-induced pulmonary fibrosis significantly increased collagen deposition and the levels of hydroxyproline (HYP) and miR-17. Interfering with miR-17 significantly reduced the levels of HYP and miR-17 and upregulated the expression of Mfn2. The intravenous injection of the miR-17 antagomir alleviated lung inflammation and reduced collagen deposition. In addition, interference with miR-17 could upregulate LC3B expression, downregulate p62 expression, and improve mitochondrial structure. Conclusion Interfering with miR-17 can improve pulmonary fibrosis in mice by promoting mitochondrial autophagy via Mfn2.
研究领域:
肺病学
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分子生物学
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病理学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Yi Zhao,Yuan-Hang Chang,Hao-Ran Ren,Ming Lou,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Shuo Liu,Yu-Sheng Shi,Hong-Mei Zhu,Jin-Long Li
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
研究领域:
神经科学
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毒理学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
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IF 8
Zi Li,Zhi Li,Qiubo Li,Ronghui Miao,Yuchao Ma,Silei Wei,Junnan Mao,Xuan Wang,Xiangtao Zeng,Yi Zhou,Jingjing Ye,Weidong Xia,Cai Lin,Cong Mao
Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain insufficient, increasing attention has been directed toward mitophagy, a key regulator of energy balance and stress responses, with mitochondrial dysfunction recognized as a critical driver of defective repair. In this study, we explored the therapeutic role of echinacoside (Ech), a phenylethanol glycoside from Echinacea , known for its potent antioxidant, anti-inflammatory, and pro-angiogenic properties, in promoting diabetic wound healing. Network pharmacology analysis was employed to identify the potential targets of Ech in diabetic condition. In vitro, under H 2 O 2 -induced oxidative stress, Ech mitigated the functional impairment of human umbilical vein endothelial cells (HUVECs), enhancing their proliferation, migration, angiogenesis, and antioxidant capacity. Mechanistically, Ech restored HUVECs function by activating Parkin-MFN2-mediated mitophagy through ubiquitination and concurrently upregulated USP35 expression, which mitigated excessive mitophagy. These effects were confirmed using the Parkin-dependent mitophagy inhibitor cyclosporin A (CsA) and USP35-specific siRNA (siUSP35). In a diabetic mouse full-thickness cutaneous wound model, Ech treatment significantly activated Parkin-dependent mitophagy, leading to enhanced neovascularization and collagen deposition at wound site, thereby accelerated the healing process of diabetic wounds. Collectively, these findings identify Ech as a promising therapeutic agent for diabetic wound repair and provide mechanistic insights into its regulation of mitophagy to improve antioxidant responses and angiogenesis, offering a foundation for the development of targeted treatment strategies.
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PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Jiafeng Wang,Daijie Xie,Xiaozhang Qu,Tian Li,Xiuping Meng,Zhimin Zhang,Yongdong Jin,Guohua Qi
Mitochondrial fusion protein 2 (Mfn2) as a molecular gatekeeper in mitochondria plays a momentous role in regulating mitochondrial morphology and function to further influence cell behavior. However, ultrasensitive and in situ measurement of low-abundance Mfn2 at the single-cell level remains a challenge, especially during external stress. Herein, an ultrasensitive and “turn-on”-type immunoassay platform for analysis of Mfn2 expression at the single-cell level during the dental pulp stem cell (DPSC) differentiation process was exploited through surface-enhanced Raman spectroscopy (SERS) as a readout modality. In this system, the detection sensitivity of Mfn2 is markedly enhanced through the generation of gap-plasmon “hot spots” caused by the biocoded SERS nanoprobes consisting of AuNPs and AgNPs following the affinity binding of Mfn2. The developed SERS immunoassay exhibited a wide linear relationship for Mfn2, ranging from 0.5 ng/mL to 5 μg/mL. Notably, the biocoded plasmonic nanoprobes reacting with Mfn2 can self-assemble to form an SERS immunoassay biosensor within single cells, which enabled sensitive measurement of Mfn2 expressions during the DPSC differentiation process evoked by electric-impulse stimulation (EIS). Mechanistically, the Mfn2 expression within DPSCs showed palpable downregulation during the EIS-induced differentiation process. The work revealed at the single-cell level a previously unknown role of Mfn2 in DPSC differentiation during the EIS process. The developed SERS immunoassay sensing platform is promising for the early diagnosis of diseases associated with Mfn2.
研究领域:
生物医学工程
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分析化学
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细胞生物学
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纳米技术
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干细胞研究
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PubMed
高影响因子
NEUROBIOLOGY OF DISEASE
·
2025
·
IF 5.6
Shiyuan Xiao,Yue Li,Jun Wang,Mengran Wang,Bing Bu,Wenmin Jiang
Elevated intraocular pressure (IOP) imposes a substantial glycolytic demand on retinal tissue, driving excessive lactate production to sustain neuronal energy homeostasis. In the present study, we demonstrate that this metabolic stress markedly increases histone H4 lysine 8 lactylation (H4K8la) throughout the glaucomatous retina. Genome-wide profiling using Cleavage Under Targets and Tagmentation (CUT&Tag) revealed pronounced and selective H4K8la enrichment within the promoter region of mitofusin-2 (MFN2), a key mitochondrial fusion GTPase. Functionally, suppression of MFN2 mediated by H4K8la reciprocally enhances β-catenin expression, particularly under oxidative stress, indicating the existence of a lactate-responsive epigenetic circuit that couples mitochondrial dynamics to activation of the Wnt/β-catenin signaling pathway. In vivo experiments demonstrated that activated Müller glia orchestrate synchronous mitochondrial remodeling in retinal ganglion cells (RGCs) and photoreceptors. We propose that MFN2 functions as a molecular conduit, enabling intercellular mitochondrial transfer between Müller glia and neurons to sustain elevated glycolytic flux. This metabolic reprogramming increases lactate release, stimulates Wnt/β-catenin pathway activation, and ultimately leads to RGC apoptosis. Single-cell RNA sequencing (scRNA-seq) further revealed intensified Müller–amacrine/bipolar cell communication under ocular hypertension, accompanied by a marked reduction in neurexin- and VEGF-mediated interactions. Collectively, these findings identify a lactylation-governed epigenetic checkpoint that links mitochondrial dysfunction to glial–neuronal metabolic coupling in glaucoma, nominating MFN2 as a potential neuroprotective therapeutic target.
研究领域:
眼科学
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表观遗传学
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代谢学
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神经科学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
AQUACULTURE NUTRITION
·
2025
·Vol. 2025
·期 1
·1151656
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IF 3.9
Nan-Jun Hu,Guang-Li Feng,Xiao-Hong Lai,Mo Peng,Yu-Feng Song
With the increasing prevalence of high-fat diets (HFD) in aquaculture practices, the detrimental effects of HFD on farmed fish have garnered significant attention. Creatine has emerged as a promising green feed additive for aquaculture species; however, its potential role in mitigating the negative impacts of HFD remains poorly understood. To address this knowledge gap, the present study was designed to investigate the protective effects of dietary creatine supplementation on HFD-induced hepatic lipid metabolism disorders and muscle quality deterioration in juvenile grass carp ( Ctenopharyngodon idella ). Three experimental diets were formulated: a control diet (5.20% lipid, control), a HFD (8.11% lipid, HFD), and a HFD supplemented with 2% creatine (HFD + creatine). Juvenile grass carp (initial weight: 4.12 ± 0.02 g) were randomly allocated into nine 300-L indoor tanks and fed the experimental diets for 8 weeks. The key findings of this study revealed that (1) Dietary creatine supplementation significantly ameliorated the adverse effects of HFD on growth performance and feed utilization efficiency in juvenile grass carp. (2) Creatine supplementation improved muscle quality parameters in juvenile grass carp. (3) Dietary creatine attenuated HFD-induced hepatic lipid accumulation through enhanced fatty acid β -oxidation, which was mediated by mfn2-dependent mitochondrial fusion. Notably, this study elucidates a novel molecular mechanism whereby creatine activates mitochondrial fusion through the binding of pparα transcription factor to specific sites on the mitofusin 2 (Mfn2) gene promoter. To our knowledge, this is the first comprehensive investigation from a multi-organ/tissue perspective combined with mitochondrial dynamics analysis, providing valuable insights for developing effective nutritional strategies to counteract HFD-induced adverse effects in farmed fish through creatine supplementation.
研究领域:
水产养殖学
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分子生物学
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营养学
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PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2024
·
IF 3.5
Wang Liwei,Zhang Lu,Yun Yang,Liang Tingting,Yan Chaoqun,Mao Zhuoya,Zhang Jingfang,Liu Baoshe,Zhang Jian,Liang Taigang
Occupational and unintentional exposure of zinc oxide nanoparticles (ZnONPs) raises concerns regarding their neurotoxic potential and there is an urgent need for the development of effective agents to protect against the toxic effects of ZnONPs. Astragalus memeranaceus (AM), a famous Traditional Chinese Medicine, as well as its bioactive components, showing a potential neuroprotective function. This study aims to investigate the neuroprotective effects of bioactive components of AM against ZnONPs-induced toxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. The cell apoptosis, ROS generation, MMP changes, mitochondrial fission/fusion, biogenesis, and mitophagy were assessed. In this study, AM treatment inhibited ZnONPs-induced cell apoptosis and ROS overproduction in SH-SY5Y cells. And astragaloside IV (ASIV) played a dominant role in the attenuation of cytotoxicity after ZnONPs exposure, rather than flavonoids and polysaccharides. ASIV treatment significantly reduced ROS generation and MMP collapse in ZnONPs-exposed cells. Furthermore, the protein expressions of mitochondrial biogenesis (PGC-1α), fusion (Mfn1 and Mfn2), and fission (Drp1) were markedly increased. Meanwhile, the PINK1/Parkin-mediated mitophagy was activated after ASIV administration, which ameliorated ZnONPs-induced SH-SY5Y cell death. Collectively, ASIV administration mitigated ZnONPs-induced cytotoxicity in SH-SY5Y cells through restoring mitochondrial quality control process, which hinted the protective role of ASIV in ZnONPs-induced neurotoxicity. Graphical abstract
研究领域:
药理学
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毒理学
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神经科学
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细胞生物学
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PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Luo Zhuo,Liu Li-Fang,Wang Xiao-Hua,Li Wen,Jie Chong,Chen Huan,Wei Fan-Qin,Lu Dan-Hua,Yan Chang-Yu,Liu Bo,Kurihara Hiroshi,Li Yi-Fang,He Rong-Rong
Stress has been proven to modulate an individual’s immune system through the release of pituitary and adrenal hormones such as the catecholamines, growth hormone, and glucocorticoids. These signal molecules can significantly alter the host immune system and make it susceptible to viral infection. In this study, we investigate whether epigoitrin, a natural alkaloid from Isatis indigotica, provides protection against influenza infection by reducing the host’s susceptibility to influenza virus under stress and its underlying mechanism. To support it, the mouse restraint stress model and the corticosterone-induced stress model were employed. Our results demonstrated that epigoitrin significantly decreased the susceptibility of restraint mice to influenza virus, evidenced by lowered mortality, attenuated inflammation, and decreased viral replications in lungs. Further results revealed that epigoitrin reduced the protein expression of mitofusin-2 (MFN2), which elevated mitochondria antiviral signaling (MAVS) protein expression and subsequently increased the production of IFN-β and interferon inducible transmembrane 3 (IFITM3), thereby helping to fight viral infections. In conclusion, our study indicated that epigoitrin could reduce the susceptibility to influenza virus via mitochondrial antiviral signaling.
研究领域:
免疫学
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病毒学
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药理学
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DOI
PubMed
高影响因子
Food & Function
·
2018
·Vol. 9
·期 12
·6349-6359
·
IF 3.289
Ying Chen,Jianjun Chen,Xiaoxue Sun,Xiaoxiao Shi,Lei Wang,Liyong Huang,Wenke Zhou
(−)-Epigallocatechin-3-gallate (EGCG), the main bioactive component of tea catechins, exhibits broad-spectrum health efficacy against mitochondrial damage after subarachnoid hemorrhage (SAH). The mechanisms, however, are largely unknown. Here, the ability of EGCG to rescue mitochondrial dysfunction and mitochondrial dynamics following the inhibition of cell death was investigated by using in vitro and in vivo SAH models. EGCG blocked the cytosolic channel ([Ca2+])i influx via voltage-gated calcium channels (VGCCs), which induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. As expected, EGCG ameliorated oxyhemoglobin (OxyHb)-induced impairment of mitochondrial dynamics by regulating the expression of Drp1, Fis1, OPA1, Mfn1, and Mfn2. As a result, EGCG restored the increases in fragmented mitochondria and the mtDNA copy number in the OxyHb group to almost the normal level after SAH. In addition, the normal autophagic flux induced by EGCG at both the initiation and formation stages regulated Atg5 and Beclin-1 after SAH for the timely elimination of damaged mitochondria. In the end, EGCG increased the neurological score by decreasing cell death through the cyt c-mediated intrinsic apoptotic pathway. The results revealed the mechanisms behind the neuroprotective effects of EGCG via inhibition of the overloaded [Ca2+]i-induced mitochondrial dysfunction and the imbalanced mitochondrial fusion and fission cycle. Therefore, the simultaneous inhibition and timely elimination of damaged mitochondria could determine the therapeutic effect of EGCG.
研究领域:
神经保护
·
线粒体生物学
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神经病学
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药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2019
·Vol. 63
·期 14
·1801432
·
IF 4.653
Lele Yang,Jinchao Wei,Feiya Sheng,Peng Li
Scope Saturated free fatty acids (FFAs) induce hepatocyte lipotoxicity, wherein oxidative stress–associated mitochondrial dysfunction is mechanistically involved. Chlorogenic acid (CGA), a potent antioxidant and anti-inflammatory compound, protects against high-fat-diet-induced oxidative stress and mitochondrial dysfunction in liver. This study investigates whether CGA protects against FFA-induced hepatocyte lipotoxicity via the regulation of mitochondrial fission/fusion and elucidates its underlying mechanisms. Methods and results AML12 cell, a non-transformed hepatocyte cell line, is treated with palmitate. Here, it is shown that CGA prevents palmitate-induced lipotoxicity by activation of SIRT1 regulated mitochondrial morphology. CGA treatment mitigates oxidative stress and mitochondrial dysfunction, as evidenced by a decrease in reactive oxygen species (ROS) production, and an increase in mitochondrial mass and mitochondrial membrane potential. CGA also significantly decreases Bax expression and thereby reduces mitochondria-mediated caspase-dependent apoptosis. Mechanistically, CGA attenuates ROS-induced mitochondrial fragmentation by inhibiting dynamin-related protein 1 (Drp1) and enhancing Mfn2 expression. In contrast, the inhibitory effects of CGA on the generation of mitochondrial ROS and Drp1 are blocked by siRNA knockdown of SIRT1. Conclusion Collectively, these findings show that supplementation with CGA protects hepatocytes from FFA-induced lipotoxicity through activation of SIRT1, which reverses the oxidative stress and dysfunction of mitochondrial biogenesis directly.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
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