Autophagy
·
2024
·
IF 14.6
Qingyuan Zhang,Chunhui Chen,Ye Ma,Xinyi Yan,Nianhong Lai,Hao Wang,Baogui Gao,Anna Meilin Gu,Qinrui Han,Qingling Zhang,Lei La,Xuegang Sun
Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.
研究领域:
肿瘤学
·
细胞生物学
·
肌肉生物学
✓ 已验证
DOI
PubMed
高影响因子
Brain Structure & Function
·
2024
·Vol. 229
·期 7
·1617-1629
·
IF 2.7
Omholt Stig W.,Lejneva Raissa,Donate Maria Jose Lagartos,Caponio Domenica,Fang Evandro Fei,Kobro-Flatmoen Asgeir
In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment.
研究领域:
神经科学
·
分子生物学
✓ 已验证
DOI
高影响因子
Human Cell
·
2025
·Vol. 38
·期 2
·1-16
·
IF 3.1
Zhang Lexi,Ye Jianfeng,Qiu Cheng
Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Twist-related protein 2 (Twist2) is a basic helix/loop/helix transcription factor. However, the underlying effects of Twist2 in IRI remain to be elucidated. Herein, we found that the expression of Twist2 was significantly upregulated in renal tissues of mice induced by ischemia/reperfusion (I/R) and in human renal tubular epithelial cell HK-2 exposed to hypoxia–reoxygenation. We silenced Twist2 with RNAi technology. Twist2 knockdown alleviated renal pathological damage in mice. Twist2 depletion ameliorated IRI-induced mitochondrial dysfunction, such as increasing ATP content and mitochondrial DNA copy number and restoring mitochondrial membrane potential in the kidneys of mice , and similar results were observed in in vitro experiments. Twist2 interference increased the expression of LC3B and decreased the expression of p62 and mitochondrial membrane proteins TIMM23 and TOMM20 both in vivo and in vitro. Electron microscope and the co-localization of LC3B and mitotracker DsRed suggested the induction of autophagy and mitophagy after Twist2 knockdown in kidneys or cells. Mechanism studies revealed that Twist2 exerted a direct inhibitory effect on BCL2 interacting protein 3 (Bnip3) transcriptional activity by targeting the Bnip3 promoter. In hypoxia/reoxygenation-induced renal tubular epithelial cells, the interference of Bnip3 reversed the effect of Twist2 depletion on mitochondrial function and mitophagy. In conclusion, our findings suggest that the depletion of Twist2 exerts renoprotective effect in I/R-induced AKI. Twist2 regulates mitochondrial function and mitophagy in part by targeting and downregulating Bnip3. Our study provides new insights into the pathological mechanisms of I/R-induced AKI.
研究领域:
肾病学
·
分子生物学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2024
·
IF 9.2
Zeying Zhang,Di Yang,Xiaoyuan Yan,Qiujing Qiu,Jiajie Guo,Lihong Qiu
Background Differentiating dental pulp stem cells (DPSCs) into odontoblasts is a critical process for tooth self-repair and dentine‒pulp engineering strategies in the clinic. However, the mechanism underlying the regulation of DPSC odontoblastic differentiation remains largely unknown. Here, we demonstrated that BCL-2 interacting protein 3 (BNIP3)-dependent mitophagy is associated with importin subunit beta-1 (KPNB1)-activating transcription factor 4 (ATF4), which promotes DPSC odontoblastic differentiation. Methods The key genes involved in DPSC odontogenic differentiation were identified via bioinformatics. Stable silencing or overexpression of BNIP3 was performed to investigate its impact on DPSC differentiation in vitro ( n ≥ 3). To explore the role of BNIP3 in vivo, tooth root fragments loaded with the hydrogel-transfected DPSC complex were implanted into nude mice ( n ≥ 6). Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) polymerase chain reaction (PCR) were conducted to explore the binding site of ATF4 to the BNIP3 promoter ( n ≥ 3). Mitochondrial function experiments were performed to investigate the impact of ATF4-BNIP3 on mitochondria ( n ≥ 3). Immunoprecipitation (IP) mass spectrometry (MS) was used to investigate the interaction between ATF4 and its binding protein, KPNB1. Plasmids containing wild-type (WT)/mutant (MUT)-nuclear localization signal (NLS) forms of ATF4 were constructed to determine the specific amino acid residues recognized by KPNB1 and their effects on DPSC odontoblastic differentiation ( n ≥ 3). Results Compared with those in the control group, the levels of autophagy and mitophagy, especially BNIP3-dependent mitophagy, were greater in the DPSC odontoblastic differentiation group ( P < 0.05). Genetic silencing or overexpression of BNIP3 demonstrated that BNIP3 expression was positively correlated with the transition of DPSCs into odontoblasts both in vitro and in vivo ( P < 0.05). ATF4 regulates the expression of BNIP3 by directly binding to approximately −1292 to −1279 bp and approximately −1185 to −1172 bp within the BNIP3 promoter region, which is associated with mitophagy and mitochondrial reactive oxygen species (mtROS) levels ( P < 0.05). Moreover, ATF4 increased mitophagy, mitochondrial function, and cell differentiation potential via BNIP3 ( P < 0.05). Mechanistically, KPNB1 is a novel interacting protein of ATF4 that specifically recognizes amino acids (aa) 280–299 within ATF4 to control its translocation into the nucleus and subsequent transcription and differentiation processes ( P < 0.05). Conclusions We reported that the critical role of KPNB1/ATF4/BNIP3 axis-dependent mitophagy could provide new cues for the regeneration of the dental pulp‒dentin complex in DPSCs. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s11658-024-00664-9.
研究领域:
牙科学
·
干细胞生物学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 7
·1-18
·
IF 8.1
Wang Sikai,Cheng Hongxia,Li Miaomiao,Gao Dongmei,Wu Haoran,Zhang Shanshan,Huang Yilan,Guo Kun
An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells’ competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2026
·
IF 4.8
Jiawei Lei,Yushan Li,Mingxin Bai,Haoyue Du,Xueqin Shen,Hu Fu,Zhengli Yan,Yongfei Zhu
Xenobiotics such as pesticides can easily damage the reproductive organs during adolescence. Dinotefuran, the latest neonicotinoid insecticide, is considered to have low toxicity in vertebrates. However, research on its reproductive toxicity, especially damage to the female reproductive system in mammals is scarce. In this study, in vivo uterine toxicity was induced by oral administration of dinotefuran to mice at a dose ≥1/2 ADI (0.1 mg/kg/day), while in vitro toxicity was resulted from exposing cultured uteri to dinotefuran at levels equivalent to human blood levels (30–6000 ng/L). Hematoxylin-eosin staining revealed that dinotefuran caused uterine damage both in vivo and in vitro , while transmission electron microscopy detected mitophagy in the uterine cells. Furthermore, this study confirmed that dinotefuran triggered oxidative stress (decreased SOD and GSH, and elevated MDA), reduced mtDNA, and disrupted the BAX-to-BCL ratio in the uterus. Double immunofluorescence, qPCR, and western blot analyses found that dinotefuran induced excessive PRKN-independent mitophagy regulated by BNIP/NIX in the uterus, along with activation of NF-κB/NLRP3 signaling and the necroptosis pathway. It also revealed that dinotefuran increased uterine Caspase-1 /Cleaved CASPASE-1 levels by qPCR and western blot analysis. Collectively, these findings indicate that dinotefuran at concentrations ≥1/2 ADI value or equivalent to human blood levels induces mouse uterine toxicity in vivo and in vitro , respectively, and they all trigger oxidative stress, BNIP3/NIX-mediated mitophagy, NF-κB/NLRP3 signaling, and necroptosis in the uterus.
✓ 已验证
产品关联
DOI
高影响因子
PHARMACOLOGICAL RESEARCH
·
2026
·
IF 12.2
Ning Yang,Yuan Qiao,Jing Wu,Chao Niu,Jianpeng Wang,Shiming Sun,Chunyan Liu,Jingtao Chen,Shan Zhu
SLMO2 is upregulated by chemotherapeutics and reduces GBM chemosensitivity. • SLMO2 mediates TMZ- and H 2 O 2 -induced mitophagy in GBM cells. • SLMO2 transcriptionally upregulates the mitophagy receptor BNIP3. • SLMO2 promotes BNIP3 via the ROS–NF-κB–HIF-1α signaling axis. Glioblastoma (GBM) is a highly aggressive malignancy, with chemoresistance acting as a major hurdle that severely limits clinical efficacy and long-term prognosis. Mitophagy, a core mechanism of mitochondrial quality control, enables tumor cells to adapt to chemotherapy-induced stress and maintain survival. However, its regulatory mechanism in GBM chemoresistance remains poorly understood. Here, we identify SLMO2 as a key factor mediating chemoresistance in GBM. Low-dose TMZ induces protective mitophagy, whereas SLMO2 knockdown abrogates this autophagic defense, thereby sensitizing GBM cells to TMZ-induced apoptosis. Mechanistically, TMZ treatment upregulates SLMO2, which potently activates HIF-1α signaling to transcriptionally drive BNIP3-mediated mitophagy, a process dependent on ROS-NF-κB signaling. Notably, this SLMO2-mediated cascade is also engaged under cisplatin-induced stress, indicating a broader role in chemoresistance. Collectively, our findings reveal that SLMO2 promotes chemoresistance in GBM by regulating BNIP3-mediated mitophagy. Targeting SLMO2 disrupts mitochondrial homeostasis by this process, offering a novel therapeutic strategy for enhancing chemosensitivity in GBM. Download: Download high-res image (228KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Arabian Journal of Chemistry
·
2022
·
IF 6.212
Zizhen Zhao,Chen Fu,Yuping Zhang,Yingying Zhang,Xiaoxi Yang,Ailing Fu
The incidence of HCC continues to increase rapidly in recent years. the principle of developing anti-HCC drugs is to specifically kill tumor cells, without affecting the function of normal cells. Here we synthesized a novel protonic compound bis(5-amino-1,10-phenanthroline) (P-BAP), and the antitumor activity was explored in vitro and in vivo . The results showed that P-BAP could selectively inhibit the proliferation of tumor cells, and induce HCC apoptosis. In HCC-bearing mice, P-BAP could effectively retard the tumor growth, even completely eliminate the tumors at the dose of 5 mg/kg, and meanwhile P-BAP had no significant effect on mouse body weight. Mechanism analysis revealed that P-BAP could down-regulate the protein expressions of pleomorphic adenoma gene like-2 (PLAGL2), HIF-1α and β-catenin, and up-regulate the levels of pro-apoptotic protein BAX and BNIP3. In addition, P-BAP could reduce mitochondrial respiratory chain complex activities, leading to insufficient ATP production. The study provides a new approach for designing selective antitumor drugs, and suggests that P-BAP would be a potential candidate for HCC therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 7
·824
·
IF 8.2
Xiaoqing Feng,Xiao Zhou,Shushan Jia,Jingzhen Chen,Peiwang Li,Yan Yang,Wei Wu,Lijuan Jiang,Wenbin Zeng,Changzhu Li,Qiang Liu,Yunzhu Chen
Camelliasaponins, bioactive constituents abundant in the by-products ofCamellia oleiferaoil production, exhibit diverse biological activities. However, their potential in regulating neuroprotective mitophagy remains largely unexplored. This study identifies camelliasaponin B1 (CSB1) as an abundant component inC. oleiferaseeds and investigates its cytoprotective mechanisms against oxidative stress. Using an in vitro model of H2O2-induced oxidative damage in PC12 cells, we found that CSB1 pretreatment significantly alleviated oxidative stress, as evidenced by reduced reactive oxygen species (ROS) accumulation and enhanced antioxidant enzyme activities (SOD, CAT, GSH-Px). CSB1 also preserved mitochondrial function, restoring membrane potential (ΔΨm), ultrastructure, and respiratory capacity. Mechanistically, CSB1 reduces the expression of BNIP3/NIX-LC3B pathway-related proteins, suggesting a modulatory effect on mitophagy, as supported by transcriptomic analysis, Western blotting, and immunofluorescence. Molecular docking computationally predicted potential interactions between CSB1 and BNIP3/NIX proteins, which require experimental validation. Collectively, these findings suggest that CSB1 acts as a cytoprotective agent that enhances antioxidant defenses, safeguards mitochondrial integrity, and is associated with reduced BNIP3/NIX-LC3B expression and co-localization, offering a potential molecular basis for its development as a neuroprotective agent targeting oxidative stress-related mitochondrial dysfunction.
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）