Cell Death & Disease
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2026
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IF 12.2
Lv Jinpeng,Xu Wenhui,Jiang Peiwen,Yu Wenhao,Xue Hui,Hu Nan,Cao Yan,Zhang Huansha,Yin Chuanwei,Gao Rongyin
Vitiligo is an autoimmune depigmenting disorder in which oxidative stress is considered a critical trigger of innate immune activation. Although keratinocytes are increasingly recognized as key contributors to disease progression, the mechanism by which they sense and propagate oxidative stress signals has remained unclear. Here, we identify mitochondrial DNA (mtDNA) release as a pivotal event linking oxidative stress to immune activation in keratinocytes. We demonstrate that hydrogen peroxide induces a sequential mitochondrial membrane remodeling process, in which mitochondrial permeability transition pore opening precedes oligomerization of the outer membrane channel protein VDAC1, enabling selective mtDNA release under non-apoptotic conditions. Escaped mtDNA acts as a danger signal that concurrently activates the cGAS–STING axis and the NLRP3 inflammasome, driving type I and type II interferon production, chemokine release, and pyroptosis. Importantly, genetic silencing or pharmacological inhibition of VDAC1 with VBIT-4 effectively blocked mtDNA release, suppressed downstream inflammatory cascades, and alleviated depigmentation and CD8⁺ T cell infiltration in a murine vitiligo model. These findings uncover a previously unrecognized mechanism by which keratinocytes transform oxidative stress into autoimmune signaling and highlight VDAC1-dependent mtDNA release as a promising therapeutic target to intercept vitiligo at an early stage.
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高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
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2023
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IF 2
Haixu Wang,Yan Li,Chuang Liu,Tianxiang Lu,Qian Zhai,Hongna Wang,Jianfang Zhang
Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 μM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.
研究领域:
生殖毒理学
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细胞生物学
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分子生物学
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Jixun Li,Ruzhen Feng,Wei Yang,Peiyao Liang,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Qiujuan Li,Guang Yang,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5–24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
研究领域:
毒理学
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细胞生物学
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环境科学
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Zhihao Xiao,Jing Jin,Xiangxing Long,Xu Zhu,Jian Jiao,Weirui Kong,Jiangzhu Li,Yuqing Zhuang,Qian Liu,Aihua Gu
This study aimed to investigate the molecular mechanism by which nickel chloride (NiCl₂) exposure promotes the progression of aortic dissection (AD), with a focus on the role of vascular smooth muscle cells (VSMCs). Through a combination of in vivo experiments using β-aminopropionitrile (BAPN)-induced AD mouse models and in vitro experiments on VSMCs, the results demonstrated that NiCl₂ exposure significantly increased the incidence of AD, enlarged the aortic diameter, and exacerbated elastic fiber damage in the aortic wall. Moreover, NiCl₂ could directly bind to the voltage-dependent anion channel 1 (VDAC1) protein on the mitochondria of VSMCs and promote its oligomerization, leading to the leakage of mitochondrial DNA (mtDNA). The leaked mtDNA activated the cGAS-STING signaling pathway in the cytoplasm, thereby inducing the phenotypic transition of VSMCs from a contractile to a synthetic state, enhancing the release of matrix metalloproteinases (MMP2, MMP9) and the expression of inflammatory factors (such as IL1β and IL6), and disrupting the structural integrity of the aortic wall. Furthermore, C-176 (a selective cGAS-STING pathway inhibitor) and STING-targeting siRNA synergistically reversed the NiCl₂-induced phenotypic transition of VSMCs, while VBIT12, an inhibitor of VDAC1, could also inhibit mtDNA leakage. This study is the first to reveal a novel mechanism by which NiCl₂ regulates VSMC dysfunction through the VDAC1-cGAS-STING axis. Our results identify NiCl 2 as a synergistic co-factor that, in conjunction with pre-existing vascular fragility (the 'first hit'), significantly accelerates AD progression through this molecular 'second hit', providing new targets and a theoretical basis for the prevention and treatment of cardiovascular diseases associated with NiCl₂ exposure.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Zefeng Jiang,Xiaowei Wen,Qin Mao,Gang Wang,Zhuo Wang,Yu Yan,Shan Gao,Xiaoqian Sun,Miao Zhang,Jiajing Liu,Rong Zhang,Baofeng Yang
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca 2+ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca 2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca 2+ overload and apoptosis by inhibiting CHOP-mediated Ca 2+ transfer between inositol 1,4,5-trisphosphate receptor (IP 3 R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP 3 R/VDAC1 signaling pathway mediates ER-mitochondrial Ca 2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca 2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease.
研究领域:
药理学
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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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高影响因子
EXPERIMENTAL CELL RESEARCH
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2024
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IF 3.3
Zhen Xu,Yilin Guo,Lu Wang,Jinquan Cui
HECW1 belongs to ubiquitin ligase (E3) HECT family, and is found to be involved in tumorigenesis and tumor progression. However, the function of HECW1 in cervical cancer (CC) remains unknown. Clinical analysis showed that HECW1 is significantly decreased in CC tumor tissues. Ectopic expression of HECW1 suppressed cell growth, promoting cell cycle arrest and apoptosis in CC cells, while downregulation of HECW1 reversed these trends, impeded proliferation and accelerated cell cycle progression of CC cells. Overexpressing of HECW1 reduced mitochondrial membrane potential and the protein expression of voltage-dependent anion channel 1 (VDAC1). In addition, upregulation of HECW1 inhibited nuclear β-catenin accumulation, downregulated β-catenin/TCF/LEF-mediated transcriptional activity and the expression of downstream gene c-Myc, whereas inhibition of HECW1 received opposite results. Further results confirmed HECW1 affects the protein expression of dishevelled-1 (DVL1), a potent activator of Wnt/β‐catenin, and inhibition of HECW1 inhibited the ubiquitination of DVL1, upregulating its expression. Inhibition of DVL1 restrained the promotion effect of HECW1 suppression on cell proliferation. In vivo experiments also verified that HECW1 suppression promoted the tumor formation of CC cells. Summary, we demonstrated that HECW1 inhibits CC cell proliferation and tumor formation by downregulating DVL1 induced Wnt/β‐catenin signaling pathway activation.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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高影响因子
BIOMATERIALS
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2023
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IF 14
Fengying Shao,Jianyu Han,Zhaoyan Tian,Zhi Wang,Songqin Liu,Yafeng Wu
Taking advantage of endogenous Ca 2+ to upregulate intramitochondrial Ca 2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca 2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca 2+ transport. It remains a great challenge to make the maximum use of endogenous Ca 2+ to ensure sufficient Ca 2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca 2+ directional transport channel to selectively transport endogenous Ca 2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe III -tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment , Fe 3+ ions are firstly released and reduced by tannic acid (TA) to Fe 2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca 2+ ions are directionally delivered and intramitochondrial Ca 2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca 2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca 2+ -involved tumor therapies.
研究领域:
肿瘤学
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药学
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生物医学工程
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高影响因子
TOXICOLOGY
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2024
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IF 4.8
Junke Wang,Yuexin Wei,Yuhao Wu,Tianxin Zhao,Lian Kang,Lindong Han,Jiadong Chen,Chunlan Long,Guanghui Wei,Lianju Shen,Shengde Wu
As one of the most prevalent environmental endocrine disruptors, di-(2-ethylhexyl) phthalate (DEHP) is known for its significant developmental toxicity to the male reproductive system in humans and mice. Prepubertal exposure to DEHP has been shown to cause testicular damage, but the underlying mechanisms require further investigation. To investigate this effect, prepubertal mice were exposed to 250 or 500 mg/kg body weight (bw) of DEHP for 14 days, which resulted in impaired histological structure and increased apoptosis of the testes. RNA sequencing (RNA-seq) of testicular tissue suggested that DEHP led to injury in Leydig and Sertoli cells. To further elucidate these mechanisms, we conducted experiments using immature mouse Leydig (TM3) and Sertoli (TM4) cells, and exposed them to 200 μM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, for 24 h. We found that MEHP exposure induced oxidative stress injury and promoted cell apoptosis, and that cotreatment with N-acetylcysteine partially reversed these injuries. Given the close association between oxidative stress and mitochondrial calcium levels, we demonstrated that MEHP exposure disrupted mitochondria and increased mitochondrial calcium levels. This effect facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), upregulated protein expression and enhanced the interactions of the IP3R3-Grp75-VDAC1 complex. Furthermore, inhibition of calcium transfer in the IP3R3-Grp75-VDAC1-MCU axis relieved MEHP-induced mitochondrial injury, oxidative stress and apoptosis in TM3 and TM4 cells. This study highlights the importance of MAM-mediated mitochondrial calcium overload and the subsequent apoptosis of Leydig and Sertoli cells as pivotal factors contributing to testicular injury induced by prepubertal exposure to DEHP.
研究领域:
环境科学
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毒理学
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生殖生物学
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细胞生物学
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内分泌学
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高影响因子
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