TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Peiwen Zhang,Shen Chen,Huanwen Tang,Wanjun Fang,Ke Chen,Xu Chen
Coenzyme Q10 (CoQ10), which is a key cofactor of the electron transport chain in the mitochondria has shown many beneficial effects on liver diseases. However, the mechanisms of CoQ10 protective role on the acetaminophen (APAP)-induced liver injury are elusive and unclear. In this study, we further investigated the CoQ10 therapeutic effects on APAP-overdose liver injury. C57BL/6 J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 1.5 h after APAP treatment. The results showed that hepatic CoQ10 levels were decreased during the APAP-induced hepatotoxicity and preceded serum ALT elevation. Treatment of CoQ10 significantly improved the liver injury induced by APAP. Moreover, CoQ10 treatment decreased the ROS levels and promoted the antioxidative related gene expression in APAP overdose mice. Importantly, results showed that even though CoQ10 had no effects on the mtDNA copy number and the expression of genes related to mitochondrial biogenesis , it significantly improved the mitochondrial complex I and V activities and promoted the mitophagy in APAP-overdose mice. To further authenticate mitophagy role in CoQ10-mediated improved liver injury in vivo, we administrated APAP-overdose mice with chloroquine 1 h prior to APAP treatment and found that chloroquine treatment functionally abrogated the CoQ10 protective role on APAP overdose mice. To conclude, this study provides evidence that CoQ10 activates mitophagy to protect against APAP-induced liver injury. Therefore, CoQ10 may represent a novel therapeutic option for the prevention and treatment of drug-induced liver injury.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Yi Wang,Nahui Liu,Lifan Hu,Jingsong Yang,Mengmeng Han,Tianjiao Zhou,Lei Xing,Hulin Jiang
Leber’s hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing it. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
研究领域:
眼科学
·
线粒体生物学
·
纳米技术
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Hao Zhang,Yi Zhao,Jia-Gen Cui,Xue-Nan Li,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used in agricultural and industrial plastic products. Many researchers have demonstrated that DEHP can cause varying degrees of harm to the heart. This research investigated the mechanism by which DEHP causes heart damage in quail. The quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day or 750 mg/kg BW/day) for 45 days. The present study suggested that DEHP could cause varying levels of heart damage, including disordered myocardial fiber arrangements, myocardial fiber breakage and myocardial cell swelling. The results showed that DEHP induced mitochondrial damage, such as cavitation lesions and mitochondrial crest breakage. DEHP damaged mitochondria and inhibited nuclear respiratory factor 1 (Nrf1)-mediated mitochondrial biogenesis, which led to mitochondrial damage. DEHP caused oxidative stress in the heart and activated the defense mechanism of the nuclear factor red blood cell 2 related factor 2 (Nrf2) system. DEHP-induced mitophagy was related to a decline in mitochondrial biogenesis and disordered mitochondrial dynamics. The data indicated that DEHP exposure damaged cardiac mitochondria and caused mitophagy and cardiotoxicity. Of note, this study showed that DEHP-induced mitophagy and mitochondrial damage are associated with the dysregulation of mitochondrial biogenesis.
研究领域:
毒理学
·
心脏病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
IF 4.872
Yuliang Xu,Xiaozhou Wang,Na Geng,Yiran Zhu,Shuo Zhang,Yongxia Liu,Jianzhu Liu
Cr (VI), which is a common heavy metal pollutant with strong oxidizing property, exists widely in nature. Organisms can be exposed to Cr (VI) through various means. Cr (VI) causes mitochondrial dysfunction after being absorbed by cells. Whether Cr (VI) induces the selective autophagic degradation of mitochondria, which is a biological process called mitophagy, remains unclear. Mitophagy not only recycles intracellularly damaged mitochondria to compensate for nutrient deprivation but also is involved in mitochondria quality control. Thus, this study investigated whether Cr (VI) could induce mitophagy in DF-1 cells. Carbonyl cyanide m-chlorophenylhydrazone, which is a mitochondrial-uncoupling reagent that induces mitophagy, was used. DF-1 cells were incubated with different doses of Cr (VI) for varying durations. The autophagy-related proteins LC3-II and p62 levels decreased after 6 h of Cr (VI) treatment but recovered within 24 h. The mitochondrial membrane potential, which is an indicator of mitochondrial damage, was detected by flow cytometry. We found that different durations of Cr (VI) treatment induced mitochondrial mass decrease and depolarization. Furthermore, the expression of the protein translocase of outer mitochondrial membrane 20 (TOMM20), which is a mitochondrial outer membrane protein, was decreased significantly in the presence of Cr (VI). Our findings indicate that Cr (VI) may contribute to the mitochondrial morphology and function damage and may therefore lead to the autophagic clearance of mitochondria.
研究领域:
毒理学
·
细胞生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Cai Haiqing,He Junxiu,Zheng Wanting,Cheng Hong,Ge Xiaoting,Bao Yu,Wei Yue,Zhou Yanfeng,Liang Xiaolin,Chen Xing,Liu Chaoqun,Wang Fei,Yang Xiaobo
Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity. Graphical
研究领域:
毒理学
·
神经科学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
·
IF 2.466
Huanan Wang,Wenqing Xu
Due to higher transmembrane potential of tumor cells, enhanced accumulation of cationic drugs in tumor mitochondria has been attributed to a higher (more negative inside) mitochondrial transmembrane potential compared with normal cells, emerging researchers are focus on developing mitochondria-targeted antitumor drugs. Coumarins showed great potential on antitumor, but mitochondria-targeted coumarin derivatives have not been reported. In the present study, we synthesized mitochondria-targeted-methyl coumarin (mito-methyl coumarin) through coupling 6-methyl coumarin to TPP. We confirmed that mito-methyl coumarin inhibited HeLa cells proliferation selectively, induced ROS generation, reduced mitochondrial membrane potential , promoted mitochondria Ca 2+ accumulation, decreased mitochondria mass and induced HeLa cells apoptosis, but methyl coumarin did not. These results demonstrate that we succeed in synthesizing a novel mitochondria-targeted drug, mito-methyl coumarin, which is effective in inhibiting HeLa cells proliferation and inducing HeLa cells apoptosis through promoting ROS generation and mitochondria Ca 2+ accumulation.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Bendong Shi,Qiaohan Liu,Chenchen Xu,Ziwei Zhang,Jingzeng Cai
Chlorantraniliprole (CAP) is a bis-amide pesticide used for pest control mainly in agricultural production activities and rice-fish co-culture systems. CAP residues cause liver damage in non-target organism freshwater fish. However, it is unclear whether CAP-exposure-induced liver injury in fish is associated with mitochondrial dysfunction-mediated mitophagy, ferroptosis, and cytokines. Therefore, we established grass carp hepatocyte models exposed to different concentrations of CAP (20, 40, and 80 μM) in vitro. MitoSOX probe, JC-1 staining, immunofluorescence double staining, Fe 2+ staining, lipid peroxidation staining, qRT-PCR, and Western blot were used to verify the physiological regulatory mechanism of CAP induced liver injury. In the present study, the CAP-treated groups exhibited down-regulation of antioxidant-related enzyme activities and accumulation of peroxides. CAP treatment induced an increase in mitochondrial reactive oxygen species (mtROS) levels and altered expression of mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2, and Opa1) genes in grass carp hepatocytes. In addition, mitophagy (Parkin, Pink1, p62, LC3II/I, and Beclin-1), ferroptosis (GPX4, COX2, ACSL4, FTH, and NCOA4), and cytokine (IFN-γ, IL-18, IL-17, IL-6, IL-10, IL-1β, IL-2, and TNF-α)-related gene expression was significantly altered. Collectively, these findings suggest that CAP exposure drives mitophagy activation, ferroptosis occurrence, and cytokine homeostasis imbalance in grass carp hepatocytes by triggering mitochondrial dysfunction mediated by the mtROS-mitochondrial fission/fusion axis. This study partly explained the physiological regulation mechanism of grass carp hepatocyte injury induced by insecticide CAP from the physiological and biochemical point of view and provided a basis for evaluating the safety of CAP environmental residues to non-target organisms.
研究领域:
毒理学
·
环境科学
·
细胞生物学
·
水生生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Yufei Wang,Yi-Feng Wang,Xianlei Li,Yuqing Wang,Qianqian Huang,Xiaowei Ma,Xing-Jie Liang
Precise subcellular manipulation remains challenging in quantitative biological studies. After target modification and hierarchical assembly, nanoparticles can be functionalized for intracellular investigation. However, it remains unclear whether nanoparticles themselves can progressively manipulate subcellular processes, especially organellar networks. Mitochondria act as the energetic supply, whose fission dynamics are often modulated by molecular reagents. Here, using different-sized gold nanoparticles (AuNPs) as a model, we demonstrated the nanoparticle-driven controllable regulation on mitochondria. Compared with molecular reagents, AuNPs could induce size-dependent mitochondrial fission without detectable cell injury, and this process was reversible along with intracellular AuNPs’ clearance. Mechanistically, it was attributed to the AuNPs-induced enhanced organelle interactome between lysosomes and mitochondria. Lysosomal accumulation of AuNPs induced lysosomal swelling and lysosomal motility alterations, promoting mitochondrial fission through the increased “kiss” events during the “kiss-and-run” moving of the lysosome–mitochondria interactome. This study highlights the fundamental understanding to fully explore the intrinsic capability of nanoparticles by engineering their basic properties. Also, it provides practical guidance to investigate the delicate nanolevel regulation on biological processes.
研究领域:
纳米技术
·
细胞生物学
·
生物物理学
✓ 已验证
DOI
PubMed
高影响因子
CARBON
·
2022
·
IF 11.307
Shuo Guo,Yuanqiang Sun,Zhaofan Wu,Ran Yang,Lingbo Qu,Zhaohui Li
Mitochondrial viscosity and mitochondrial membrane potential (MMP) are vital parameters for reflecting mitochondrial conditions and they are closely correlative in various biological events. Accordingly, simultaneous detection of mitochondrial viscosity and MMP is imperative for elucidating their interactions, further exploring the mechanism of diseases, and investigating numerous pathological procedures. However, such profound research remains a big challenge due to the lack of high-performing single fluorescent probes capable of simultaneously visualizing of these two parameters. In this study, we developed a new kind of fluorescent carbon dots (CDs) that can successfully realize simultaneous monitoring of mitochondrial viscosity and MMP in living cells. The fluorescence of CDs can be specifically turned on as the viscosity of solvents increases from 0.89 to 945 cP. Meanwhile, the CDs accumulate in mitochondria under normal MMP conditions, switch to exist in both mitochondria and nucleoli under reduced MMP, and present only in nucleoli with the vanishment of MMP. Thus, various MMP situations can be easily differentiated through the changed spatial distributions of CDs. More importantly, based on the developed CDs, an increased mitochondrial viscosity accompanying a decreased MMP was simultaneously tracked in drug-stimulated cells. We envision that the developed CDs has a great potential to be utilized as a promising fluorescent probe for mitochondrion-related biology studies.
研究领域:
生物化学
·
细胞生物学
·
医学诊断
✓ 已验证
产品关联
DOI
高影响因子
Science China-Life Sciences
·
2024
·
IF 8
Wang Rui,Bao Feixiang,Lu Manjiao,Jia Xiaoyun,Xiao Jiahui,Wu Yi,Zhang Qingjiong,Liu Xingguo
Leber’s hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.
研究领域:
神经科学
·
干细胞生物学
·
线粒体遗传学
·
细胞治疗
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2025
·Vol. 82
·期 1
·1-18
·
IF 6.2
Chen Dake,Zhou Shiqin,Tang Jinhua,Xiong Hao,Li Jialian,Li Fenge
DnaJ heat shock protein family member C5 beta (DNAJC5B), also known as cysteine-string protein beta, exhibits a prominent expression in testicular tissue and plays an important role in acrosomal exocytosis in vitro. Nevertheless, the precise role and underlying mechanism of DNAJC5B in spermatogenesis and male fertility remain poorly understood. The meta-analysis of RNA-sequencing datasets from porcine and murine testes reveals that Dnajc5b could be a pivotal factor in spermatogenesis. This study illustrates that male fertility declines with an increased ratio of abnormal spermatozoa in germ-cell knockout Dnajc5b mice. DNAJC5B has been identified as a mitochondrial protein with high expression in spermatids. The absence of DNAJC5B induces a cascade of mitochondrial damages, including oxidative stress, mitochondrial stress in the testes, and lower mitochondrial membrane potential of spermatozoa. In vivo and in vitro evidence demonstrates that DNAJC5B mitigates excessive cellular autophagy and mitophagy via DNAJ domain under environmental stress conditions, such as starvation or exposure to mitochondrial uncouplers FCCP and CCCP. This study highlights the important role of DNAJC5B in safeguarding male fertility by preserving mitochondrial function and regulating autophagy during spermiogenesis.
研究领域:
生殖生物学
·
分子生物学
·
细胞生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2023
·
IF 14.5
Xiaowei Wang,Mengyan Wang,Meilian Cai,Rongguang Shao,Guimin Xia,Wuli Zhao
Pancreatic cancer is a more aggressive and refractory malignancy. Resistance and toxicity limit drug efficacy. Herein, we report a lower toxic and higher effective miriplatin (MPt)-loaded liposome, LMPt, exhibiting totally different anti-cancer mechanism from previously reported platinum agents. Both in gemcitabine (GEM)-resistant/sensitive (GEM-R/S) pancreatic cancer cells, LMPt exhibits prominent anti-cancer activity, led by faster cellular entry-induced larger accumulation of MPt. The level of caveolin-1 (Cav-1) determines entry rate and switch of entry pathways of LMPt, indicating a novel role of Cav-1 in nanoparticle entry. After endosome-lysosome processing, in unchanged metabolite, MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM, to degrade POLG and TFAM. Then, via PINK1-Parkin axis, mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA (mtDNA) replication blocking. Additionally, POLG and TFAM are identified as novel prognostic markers of pancreatic cancer, and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity. Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA (target of most platinum agents), and totally distinct mechanism of MPt and other formulations of MPt. Self-assembly offers LMPt special efficacy and mechanisms. Prominent action and characteristic mechanism make LMPt a promising cancer candidate.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
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）