Journal of Orthopaedic Surgery and Research
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2025
·Vol. 20
·期 1
·1-17
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IF 2.8
Zhang Yang,Gao Yucheng,Liu Shuanggong,Yang Guowei,Rong Yijun,Wu Dongjin,Gao Zengxin
Background Intervertebral disc degeneration (IVDD) is a multifactorial disorder and a leading contributor to chronic low back pain (LBP), highlighting the need for novel therapeutic strategies. Recent studies indicate that ferroptosis, driven by oxidative stress, plays a key role in the loss of nucleus pulposus cells (NPCs) during IVDD. Vacuole membrane protein 1 (VMP1), a membrane-associated regulator of autophagy, is known to influence various cellular processes. However, its role in IVDD remains unclear. This study investigates the function of VMP1 in IVDD and the mechanisms involved.Methods We established a rat model of IVDD to investigate the correlation between VMP1 expression and ferroptosis during IVDD progression. In vitro, a ferroptosis model of NPCs was induced using tert-butyl hydroperoxide (TBHP) to examine the effects of VMP1 knockdown on NPC apoptosis, extracellular matrix (ECM) degradation, ferroptosis, PINK1/Parkin-dependent mitophagy, and mitochondrial function. Furthermore, cyclosporin A (CsA), a mitophagy inhibitor, was employed to explore the role and potential mechanisms of VMP1 overexpression in regulating PINK1/Parkin-mediated mitophagy, mitochondrial function, and ferroptosis.Results In this study, we observed a significant downregulation of VMP1 expression in a rat model of IVDD, which was accompanied by the occurrence of ferroptosis. Subsequent experiments revealed that VMP1 knockdown aggravated apoptosis and ECM degradation in NPCs. Furthermore, we demonstrated that VMP1 silencing promoted ferroptosis, inhibited PINK1/Parkin-dependent mitophagy, and impaired mitochondrial function in NPCs. In contrast, VMP1 overexpression enhanced PINK1/Parkin-mediated mitophagy, mitigated mitochondrial dysfunction, and suppressed ferroptosis. Notably, these protective effects were abolished by treatment with CsA.Conclusion sThis study demonstrates that VMP1 alleviates IVDD by inhibiting ferroptosis and mitochondrial dysfunction in NPCs, a protective effect mediated through the promotion of PINK1/Parkin-dependent mitophagy. Our study underscores the pivotal role of VMP1 in coordinating mitophagy and ferroptosis during IVDD pathogenesis, identifying VMP1 as a potential therapeutic target for IVDD treatment.Graphical
研究领域:
生物医学
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细胞生物学
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遗传学
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PubMed
高影响因子
MICROVASCULAR RESEARCH
·
2023
·
IF 3.1
Xue Liu,Hongjiao Du,Yilong Pan,Xiaodong Li
Pathological cardiac hypertrophy is an adaptive reaction in response to pressure or volume overload. Autophagy is critical for damage caused by pathological cardiac hypertrophy. Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that is effective in activating autophagy. However, the role of VMP1 in pathological cardiac hypertrophy and its underlying mechanisms remain elusive. This study was designed to explore the potential mechanisms of VMP1 on pressure overload-induced pathological cardiac hypertrophy. In this work, abdominal aorta constriction (AAC) surgery was used to induce pathological cardiac hypertrophy in male C57BL/6 mice. H9C2 cardiomyocytes were treated with phenylephrine stimulation (PE) to induce the hypertrophic response. The in vivo results revealed that mice with AAC surgery caused pathological cardiac hypertrophy as evidenced by improved cardiac function according to multiple echocardiographic parameters. Moreover, elevated VMP1 expression was also observed in mice after AAC surgery. VMP1 knockdown aggravated changes in cardiac structure, cardiac dysfunction, and fibrosis. Meanwhile, VMP1 knockdown suppressed autophagy and endoplasmic reticulum calcium ATPase (SERCA) activity in heart tissues. H9C2 cardiomyocytes with VMP1 overexpression were used to investigate the specific mechanism of VMP1 in pathological cardiac hypertrophy, and VMP1 overexpression increased autophagic flux by upregulating SERCA activity. In conclusion, these findings revealed that VMP1 protected against pressure overload-induced pathological cardiac hypertrophy by inducing SERCA-regulated autophagic flux. Our results provide valuable insights regarding the pathophysiology of pathological cardiac hypertrophy and clues to a novel target for the treatment of pathological cardiac hypertrophy.
研究领域:
心脏病学
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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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PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2026
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IF 13.6
Zhou Chen,Bai Dongsheng,Zhao Jiawei,Yin HongJie,Du Jiaying,Gu Chunyang,Wang Yuxiang,Lin Binyan,Lu Na,Zhao Yue
The cGAS-STING signaling serves as a central hub for innate immunity by orchestrating type I interferon production and inflammatory cascades in response to cytosolic DNA. A critical rate-limiting step in this pathway involves STING exit from the endoplasmic reticulum (ER), a process initiated by COPII-mediated trafficking that requires ER membrane curvature formation. However, the molecular mechanism that drives this process is poorly understood. In this study, we identify VMP1, an ER-resident transmembrane protein, as a negative regulator that constrains STING ER exit and downstream signaling activation. VMP1 controlled ER PtdIns(3)P accumulation, which was essential for ER membrane curvature formation. Depletion of Vmp1 triggered CDIPT-dependent PtdIns(3)P synthesis through a non-canonical pathway independent of VPS34 stability and MTMR3 expression. Furthermore, VMP1-mediated macroautophagy degraded Rab10 GTPase, thereby suppressing CDIPT recruitment to the ER membrane. Myeloid-specific Vmp1 knockout mice exhibited augmented antiviral defense against DNA virus infection but displayed unaltered susceptibility to RNA virus infection. These results suggest that VMP1 controls STING trafficking by modulating the Rab10-CDIPT axis to restrict ER PtdIns(3)P accumulation and limit ER membrane curvature formation required for COPII vesicle biogenesis.
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高影响因子
Advanced Science
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2026
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IF 14.1
Jiawei Zhao,Jianjun Zou,Chen Zhou,Yingui Wang,Yiman Liu,Yanqing Zhou,Yuxiang Wang,Xinyu Zhang,Huishu Yang,Hongjie Yin,Dongsheng Bai,Yue Zhao,Na Lu
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. This disease is characterized by a steadily increasing global incidence. Multiple susceptibility genes are implicated in IBD pathogenesis. However, the molecular mechanisms linking epithelial barrier dysfunction to disease progression remain poorly understood. This study performs an integrative analysis of public bulk RNA-seq and single-cell transcriptomic datasets. Experimental validation is conducted using clinical samples. Analyses reveal that vacuole membrane protein 1 (VMP1) is significantly downregulated in IBD. This reduced expression correlates with disease severity. Functional studies demonstrate that VMP1 deficiency in intestinal epithelial cells disrupts tight junction integrity. This loss increases epithelial permeability and exacerbates intestinal inflammation. Mechanistically, VMP1 facilitates the recruitment of CORO1C to late endosomes. This recruitment promotes Retromer-mediated recycling of the tight junction protein Occludin to the plasma membrane. Impairment of this pathway shifts Occludin trafficking toward ESCRT-dependent microautophagic degradation. This shift results in the sustained loss of tight junctions. These findings identify VMP1 as a previously unrecognized regulator of epithelial tight junction recycling and barrier homeostasis. This discovery provides new mechanistic insights into IBD pathogenesis and highlights a promising therapeutic avenue for restoring intestinal barrier function.
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高影响因子
STAR Protocols
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2022
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IF 0
Lingzhi Wu,Lu Liu,Bolin Xu,Dong Huang,Xiao-Wei Chen
Summary Amphipathic phospholipids translocated by scramblases play a central role in facilitating lipid movement across the membrane bilayer, especially at the endoplasmic reticulum (ER) membranes. Here, we present a protocol for assessing the activity of the ER-localized lipid scramblase TMEM41B. We detail an in vitro fluorescent liposome-based phospholipid scrambling assay and in vivo metabolic labeling in living cells using alkyne-choline. The scramblase activity of other VTT (VMP1, TMEM41, and Tvp38) domain-containing proteins, such as TMEM41A and VMP1, can be assayed. For complete details on the use and execution of this protocol, please refer to Huang et al. (2021) .
研究领域:
细胞生物学
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分子生物学
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生物化学
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