FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Bixi Gao,Zongqi Wang,Kun Dai,Yunjiang Wang,Longyuan Li,Guangzhao Li,Xiaowang Niu,Xiang Li,Zhengquan Yu,Zhong Wang,Gang Chen
Background The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment . We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. Methods Western blot analysis , aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. Results The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo . Conclusions We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.
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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癌症研究
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2026
·
IF 4.7
Zhichao Yu,Lan Hu,Jing Ding,Xiang Li,Qi Zhang,Qiaoyu Zhang,Shuoyu Chen,Pei Zhang,Jiaqi Zhang,Baoping Jiang,Xueping Zhou,Lingling Zhou
Background The mitochondrial unfolded protein response (UPR mt ) maintains proteostasis, but its dysregulation dictates cell fate. This study aimed to elucidate the signaling mechanism by which triptolide (TP), a bioactive component of Tripterygium wilfordii Hook. f., triggers hepatocellular Lipoapoptosis, focusing on HSP60-mediated UPR mt overactivation. Methods A TP-induced mouse liver injury model was established. Serum biochemistry, histopathology, and liver proteomics were performed. Key proteins (HSP60, UPR mt components, SREBP-1c, FASN, cleaved caspase-3) were validated by Western blot and RT-qPCR both in vivo and in AML-12 hepatocytes, while co-immunoprecipitation (Co-IP) was conducted in AML-12 cells. Functional validation used siRNA knockdown. Results TP induced liver injury, lipid deposition, and apoptosis. Proteomic screening implicated UPR mt activation, with HSP60 subsequently validated as a central upregulated component. TP downregulated MFN2 and upregulated HSP60, ClpP, DRP1, SREBP-1c, FASN, and cleaved caspase-3. Co-IP confirmed a direct HSP60–SREBP-1c interaction. Moreover, HSP60 knockdown attenuated the entire TP-induced cascade, including UPR mt overactivation, mitochondrial dysfunction, lipid dysregulation, and apoptosis. Conclusion This study delineates a novel mitochondria-to-nucleus pathway wherein TP induces HSP60-mediated UPR mt overactivation, which promotes SREBP-1c/FASN-driven lipid accumulation, culminating in lipoapoptosis. The “HSP60–UPR mt –SREBP-1c/FASN–lipoapoptosis” axis links dysregulated organelle stress signaling to metabolic cell death. These findings establish HSP60 as a key signaling node and a potential therapeutic target for intercepting this pathological cascade.
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PubMed
高影响因子
Cell Death & Disease
·
2025
·
IF 9.6
Ren Yuanyuan,Cui Yue,Wang Zhen,Luo Yizhi,Jin Junchang,Yuan Yiyi,Li Xuan,Zhang Yaning,Cao Nan,Li Xiaofang,Yu Yi,Xiong Yuyan
Gastric cancer (GC) is a prevalent gastrointestinal malignancy in which ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPR mt ) and induced mitochondrial dysfunction. Restoration of UPR mt ameliorated ALDH3A2-induced mitochondrial dysfunction and ferroptosis. Mechanistically, ALDH3A2 impaired UPR mt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent ferroptosis. Synergistically, ALDH3A2-induced ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.
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PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 7
·5815-5826
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IF 4.171
Yi Zhao,Mu-Zi Li,Milton Talukder,Yu Luo,Yue Shen,Hao-Ran Wang,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant, which is mainly used as a plasticizer to improve the flexibility of products; however, its extensive use causes male reproductive damage. Lycopene (LYC) has a protective effect on male reproductive toxicity. Nevertheless, the underlying role of LYC in DEHP-induced spermatogenic cell damage remains unclear. Our study aimed to investigate the role of LYC in DEHP-induced spermatogenic cell damage and its underlying mechanism. Male ICR mice were treated with LYC (5 mg kg−1) and/or DEHP (500 mg kg−1 or 1000 mg kg−1) for 28 days. The results showed that LYC alleviated the DEHP-induced decrease in mitochondria volume density and mitochondrial membrane potential (ΔΨm). Subsequently, LYC prevented the DEHP-induced PGC-1α-mediated reduction in mitochondrial biogenesis in spermatogenic cells. LYC exhibited a potential preventive effect against DEHP-induced mitophagy caused by mitochondrial dynamics disorder in the spermatogenic cells. Meanwhile, LYC relieved DEHP-induced mitochondrial stress in the spermatogenic cells by activating UPRmt. These results proved that mitochondrial quality control may be related to the beneficial role of LYC in preventing DEHP-induced mitophagy in spermatogenic cells. This study provides new evidence of mitochondrial quality control as a target for LYC treatment, which can prevent DEHP-induced toxicity.
研究领域:
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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环境健康
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DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
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2022
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IF 13.417
Yangli Liu,Jun Zhou,Ning Zhang,Xueying Wu,Qian Zhang,Wenfeng Zhang,Xinyu Li,Ye Tian
Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPR mt ) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPR mt , leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPR mt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPR mt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.
研究领域:
细胞生物学
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神经生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
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2022
·
IF 9.995
Xinyu Li,Jiasheng Li,Di Zhu,Ning Zhang,Xusheng Hao,Wenfeng Zhang,Qian Zhang,Yangli Liu,Xueying Wu,Ye Tian
Summary Coordination of inter-tissue stress signaling is essential for organismal fitness. Neuronal mitochondrial perturbations activate the mitochondrial unfolded-protein response (UPR mt ) in the intestine via the mitokine Wnt signaling in Caenorhabditis elegans . Here, we found that the protein disulfide isomerase PDI-6 coordinates inter-tissue UPR mt signaling via regulating the Wnt ligand EGL-20. PDI-6 is expressed in the endoplasmic reticulum (ER) and interacts with EGL-20 through disulfide bonds that are essential for EGL-20 stability and secretion. pdi-6 deficiency results in misfolded EGL-20, which leads to its degradation via ER-associated protein degradation (ERAD) machinery. Expression of PDI-6 declines drastically with aging, and animals with pdi-6 deficiency have decreased lifespan. Overexpression of PDI-6 is sufficient to maintain Wnt/EGL-20 protein levels during aging, activating the UPR mt , and significantly extending lifespan in a Wnt- and UPR mt -dependent manner. Our study reveals that protein disulfide isomerase facilitates Wnt secretion to coordinate the inter-tissue UPR mt signaling and organismal aging.
研究领域:
分子生物学
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衰老研究
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细胞信号传导
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发育生物学
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DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 8
·4527-4536
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IF 6.317
Jia-Gen Cui,Yi Zhao,Hao Zhang,Xue-Nan Li,Jin-Long Li
Lycopene (LYC), as a kind of carotene, has antioxidant effects. Di(2-ethylhexyl) phthalate (DEHP) was used to improve the flexibility of plastics. However, the potential role of LYC in DEHP induced cardiac injury in mice remains unclear. Therefore, the aim of this study was to investigate the role and mechanism of LYC in DEHP induced cardiac injury. Male ICR mice were treated with DEHP (500 or 1000 mg per kg BW per day) and/or LYC (5 mg per kg BW per day) for 28 days. The results of histopathology and ultrastructure showed that LYC relieved the decrease of mitochondrial volume density and myocardial fibre disorder induced by DEHP. Subsequently, LYC attenuated DEHP-induced mitochondrial damage, mitochondrial unfolded protein response (UPRmt) activation, nuclear factor erythroid 2-related factor 2 (Nrf2) mediated oxidative stress and heat shock response (HSR) activation induced by DEHP. LYC regulates UPRmt to prevent DEHP-induced cardiac mitochondrial damage. Thus, this study provided new evidence of UPRmt as a target for LYC treatment preventing DEHP-induced cardiac disease.
研究领域:
药理学
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毒理学
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心脏病学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Huimin Liu,Panpan Chen,Xubo Yang,FanRui Hao,Guojing Tian,Zhao Shan,Bin Qi
Animals constantly face microbial challenges, and microbe-mediated infection protection is crucial for host survival. Identifying specific bacteria and their interactions with host intracellular surveillance systems is important but challenging. Here, we develop a “probiotics” screening system that identifies Escherichia coli mutants, such as ΔymcB , which protect hosts from Pseudomonas aeruginosa PA14 infection by activating the mitochondrial unfolded protein response (UPR mt ). Genetic screening reveals that MDSS-1, a neuronal transmembrane protein, is crucial for sensing ΔymcB and triggering intestinal UPR mt . MDSS-1 functions as a potential receptor in ASE neurons, detecting ΔymcB and transmitting signals through neuropeptides, GPCRs, Wnt signaling, and endopeptidase inhibitors to activate intestinal UPRmt and enhance protection. Constitutive activation of MDSS-1 in ASE neurons is sufficient to induce UPR mt and confer infection resistance. This study uncovers a neuron-intestine communication mechanism, where ASE neurons detect bacteria and modulate the intestinal mitochondrial surveillance system for host adaptation to pathogens.
研究领域:
微生物学
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神经科学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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