INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Xinyu Zhang,Haojie Liu,Yumeng Shi,Zhenhao Liu,Yan Wang,Simai Chen,Xingzhi Yan,Rongyao Xu,Junqing Ma,Qiang Chen,Shuyu Guo
Aims Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease linked to disrupted chondrocyte activity and cartilage homeostasis. This study aimed to clarify the protective role of optineurin (OPTN) in preventing chondrocyte apoptosis during TMJ OA progression. Materials and Methods Using bioinformatics analysis, Optn was identified as a key gene in chondrocyte regulation. We employed a unilateral anterior crossbite (UAC) model in vivo and Tunicamycin (TM) in vitro to investigate OPTN's role in TMJ OA. Makin scores and histological staining assessed cartilage degeneration, while flow cytometry measured chondrocyte apoptosis, mitochondrial, and endoplasmic reticulum (ER) calcium levels. Key Findings We demonstrated that OPTN deficiency accelerates arthritis progression by intensifying endoplasmic reticulum stress (ERS) and chondrocyte apoptosis both in vivo and in vitro. Mechanistically, in vitro data showed that OPTN interacted with glycogen synthase kinase 3 beta (GSK3β), modulating the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (GRP75)/voltage-dependent anion channel 1 (VDAC1) complex. This interaction affected ER-mitochondrial calcium transfer, elevating mitochondrial calcium, and promoting apoptosis. Inhibiting this calcium channel with SB216763 and 2-APB effectively reduced mitochondrial Ca 2+ overload and apoptosis. Significance These findings reveal the crucial role of OPTN deficiency in TMJ OA pathogenesis and propose that targeting the IP3R-GRP75-VDAC1 complex to alleviate mitochondrial calcium could offer new therapeutic strategies for TMJ OA.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
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IF 14.6
Jiajia Wang,Yueping Qiu,Lijun Yang,Jincheng Wang,Jie He,Chengwu Tang,Zhaoxu Yang,Wenxiang Hong,Bo Yang,Qiaojun He,Qinjie Weng
Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic – pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.
研究领域:
肝病学
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细胞生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xiaohua Dong,Jing Zhao,Dongya Jiang,Ziyi Lu,Xingdan Liu,Kaijia Tan,Kelvin W.K. Yeung,Xuanyong Liu,Liping Ouyang
Spinal cord injury is hard to repair due to the aggregated injury to neighbor cells caused by neuro-inflammation, which always results in severe outcomes. In this work, Tc peptide, which served as the antagonist of CXCR4 and the agonist of CXCR7, was loaded in a self-healing hydrogel. The hydrogel containing Tc was found to possess superior spinal cord injury repair abilities, including motor neuron regeneration, axon bridging repair and motor functions recovery, due to the inflammation inhibition. The mechanism analysis by RNA-sequencing and in vitro experiments found that the elevated ANT1 accelerates OPTN recruitment, which subsequently recognized by LC3 to form phagophore around dysfunctional mitochondria, resulting in a regressive NLRP3 expression. However, this regression was abolished after inhibiting OPTN. Beneficial from the mitophagy process, ROS was reduced and type 1 microglia activation was diminished. This positive feedback loop accelerated spinal cord injury repair. In summary, the hydrogel containing Tc could promote spinal cord injury repair through reducing neuro-inflammation via enhanced ANT1/OPTN axis mediated mitophagy, which may provide a new peptide containing hydrogel for repairing spinal cord injury.
研究领域:
神经科学
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生物医学工程
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材料科学
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药理学
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DOI
高影响因子
EXPERIMENTAL CELL RESEARCH
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2026
·Vol. 463
·期 2
·115195
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IF 3.5
Zhenyi Lu,Hao Huang,Wanshu Lv,Jingjing Yan,Yumeng Shi,Jieli Ni,Yang Zhang,Rongyao Xu,Geng Wu,Shuyu Guo
Optn loss causes severe bone defects. • OPTN is vital for craniofacial bone development and OMSC osteogenesis. • OPTN cooperates with TRIP6 to recruit F-actin for mitophagy closure. • Actin-driven mitophagy dictates ACP packaging and EV-mediated release. The development of craniofacial bones is highly dependent on the intramembranous ossification process driven by orofacial mesenchymal stem cells (OMSCs). Optineurin (OPTN), a traditional mitophagy receptor, promotes OMSC matrix mineralization by mediating the extracellular release of amorphous calcium phosphate (ACP) through the initiation of mitophagy via liquid-liquid phase separation. However, the dynamic mechanisms by which OPTN regulates mitochondrial engulfment remain elusive. In this work, we show that in both zebrafish and mouse models, Optn absence causes systemic bone loss and craniofacial abnormalities. Mechanistically, OPTN recruits thyroid receptor-interacting protein 6 (TRIP6) to the surface of damaged mitochondria, inducing local F-actin polymerization and remodeling, which relies on cytoskeletal mechanical forces to support the bending and closure of the phagophore. The depletion of OPTN or TRIP6 significantly impairs mitophagy flux, triggering a massive accumulation of dysfunctional mitochondria. Overall, this study elucidates that the OPTN-TRIP6-F-actin axis ensures autophagosome closure through cytoskeletal remodeling, revealing a novel paradigm in which cytoskeletal mechanical regulation maintains mitochondrial homeostasis to orchestrate craniofacial osteogenesis. Download: Download high-res image (615KB) Download: Download full-size image
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DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Wenxiang Hong,Hongbo Ma,Zhaoxu Yang,Jiaying Wang,Bowen Peng,Longling Wang,Yiwen Du,Lijun Yang,Lijiang Zhang,Zhibin Li,Han Huang,Difeng Zhu,Bo Yang,Qiaojun He,Jiajia Wang,Qinjie Weng
Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C–C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn -deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.
研究领域:
免疫学
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风湿病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）