FASEB JOURNAL
·
2010
·
IF 6.401
Keri A. Barksdale,Emma Perez-Costas,Johanna C. Gandy,Miguel Melendez-Ferro,Rosalinda C. Roberts,Gautam N. Bijur
Neuronal function in the brain requires energy in the form of ATP, and mitochondria are canonically associated with ATP production in neurons. The electrochemical gradient, which underlies the mitochondrial transmembrane potential (ΔΨ mem ), is harnessed for ATP generation. Here we show that ΔΨ mem and ATP-production can be engaged in mitochondria isolated from human brains up to 8.5 h postmortem. Also, a time course of postmortem intervals from 0 to 24 h using mitochondria isolated from mouse cortex reveals that ΔΨ mem in mitochondria can be reconstituted beyond 10 h postmortem. It was found that complex I of the mitochondrial electron transport chain was affected adversely with increasing postmortem intervals. Mitochondria isolated from postmortem mouse brains maintain the ability to produce ATP, but rates of production decreased with longer postmortem intervals. Furthermore, we show that postmortem brain mitochondria retain their ΔΨ mem and ATP-production capacities following cryopreservation. Our finding that ΔΨ mem and ATP-generating capacity can be reinitiated in brain mitochondria hours after death indicates that human postmortem brains can be an abundant source of viable mitochondria to study metabolic processes in health and disease. It is also possible to archive these mitochondria for future studies.—Barksdale, K. A., Perez-Costas, E., Gandy, J. C., Melendez-Ferro, M., Roberts, R. C., Bijur, G. N. Mitochondrial viability in mouse and human postmortem brain.
研究领域:
神经科学
·
细胞生物学
·
代谢研究
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2024
·
IF 6.7
Fei Peng,Xiangnan Ai,Jing Sun,Xichuan Ge,Meiqi Li,Peng Xi,Baoxiang Gao
Mitochondrial cristae, invaginations of the inner mitochondrial membrane (IMM) into the matrix, are the main site for the generation of ATP via oxidative phosphorylation, and mitochondrial membrane potential (MMP). Synchronous study of the dynamic relationship between cristae and MMP is very important for further understanding of mitochondrial function. Due to the lack of suitable IMM probes and imaging techniques, the dynamic relationship between MMP and cristae structure alterations remains poorly understood. We designed a pair of FRET-based molecular probes, with the donor (OR-LA) being rhodamine modified with mitochondrial coenzyme lipoic acid and the acceptor (SiR-BA) being silicon-rhodamine modified with a butyl chain, for simultaneous dynamic monitoring of mitochondrial cristae structure and MMP. The FRET process of the molecular pair in mitochondria is regulated by MMP, enabling more precise visualization of MMP through fluorescence intensity ratio and fluorescence lifetime. By combining FRET with FLIM super-resolution imaging technology, we achieved simultaneous dynamic monitoring of mitochondrial cristae structure and MMP, revealing that during the decline of MMP, there is a progression involving cristae dilation, fragmentation, mitochondrial vacuolization, and eventual rupture. Significantly, we successfully observed that the rapid decrease in MMP at the site of mitochondrial membrane rupture may be a critical factor in mitochondrial fragmentation. These data collectively reveal the dynamic relationship between cristae structural alterations and MMP decline, laying a foundation for further investigation into cellular energy regulation mechanisms and therapeutic strategies for mitochondria-related diseases.
研究领域:
细胞生物学
·
生物物理学
·
医学影像学
✓ 已验证
DOI
PubMed
高影响因子
AQUACULTURE
·
2021
·
IF 4.242
Xiaoping Tan,Yang Hu,Shenye Qu,Gaoxue Wang,Tianqiang Liu
Noxious pathogens always lead to high rates of mortality, which results in severe economic losses in aquaculture. Currently, gyrodactylosis treatments mainly rely on unapproved chemicals, which are not always satisfactory. According to the previous study, arctigenin is an efficient natural product for controlling gyrodactylosis. For the sake of seeking high-efficiency compounds, a new arctigenin derivative (CCA) was synthesized. Next, we evaluated the anthelmintic activity of CCA in vitro and in vivo , and studied the mechanism of action. The number of Gyrodactylus kobayashii significantly reduced as compared with the control group, the EC 50 value at 24 and 48-h after CCA treatment was 0.616 and 0.451 mg/L, respectively, with EC 100 at CCA concentration of 3 mg/L after 1 h bath treatment. In vitro results showed that CCA can rapidly reduce the amount of G. kobayashii and inhibit its mobility that could normally lead to death. The concentration and duration of CCA were positively correlated with the mortality of G. kobayashii . In addition, CCA displayed 100% efficacy against G. kobayashii at 4.0 mg/L after only 20 min exposure. Acute toxicity assay demonstrated that the LC 50 of CCA against goldfish was 5.012 mg/L, which was 8.13 times higher than that of the EC 50 . Furthermore, the results of confocal microscope study revealed that CCA leaded to the epidermal structure and dissolved muscles of worms. Moreover, the ATP level of worms were decreased sharply after both in vitro and in vivo exposures with CCA. The anthelminthic mechanism of CCA against gyrodactylids was related to epidermal structure damages and energy insufficient. From the previous study, the EC 50 of CCA against G. kobayashii (0.616 mg/L) was much lower than the EC 50 (1.85 mg/L) of arctigenin ( Tu et al., 2018 ). In summary, CCA is more effective than arctigenin and has great potential in control of Gyrodactylus infections.
研究领域:
水产养殖
·
寄生虫学
·
药理学
·
兽医学
✓ 已验证
DOI
高影响因子
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
·
2022
·Vol. 149
·期 2
·683-699
·
IF 4.322
Shen Chongxing,Yue Xiaofeng,Dai Linyong,Wang Jianwu,Li Jinjin,Fang Qiang,Zhi Yi,Shi Chunmeng,Li Weibing
Background Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer. Material and methods The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer. Results IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. Conclusion We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yuangui Tang,Chenyun Dai,Huihui Yang,Xian Yang,Ziyu Chen,Jinxiu Dou,Liuxu Zhang,Tao Bai,Junfang Zheng
Non-histone proteins localized in membrane, cytosol and nucleus are lactylated to promote tumor progression. However, whether mitochondrial proteins undergo lactylation and contribute to tumor progression remains unexplored. Here, we identified multiple lactylated mitochondrial proteins in human renal cell carcinoma (RCC) cells using lactylome profiling. Among these, malate dehydrogenase 2 (MDH2)–the only lactylated protein in the tricarboxylic acid (TCA) cycle–emerged as a key target, with K239 as its lactylation site. MDH2 K239la levels are regulated by KAT8 and SIRT3. Under low-glucose, high-lactate conditions mimicking the tumor microenvironment, MDH2 K239la elevated the NADH/NAD + ratio to drive ATP production and boosted NADPH generation to reduce ROS. This enables cells to alleviate oxidative stress, sustain mitochondrial function, and promote RCC malignancy in vitro and in vivo . Mechanistically, MDH2 K239la enhances MDH2 enzymatic activity and strengthens its interaction with the citrate transporter SLC25A1. This facilitates citrate efflux, fueling IDH1-dependent NADPH production when lactate serves as an energy source. Collectively, we unveil a lactylation-dependent mechanism that reprograms mitochondrial metabolism to confer oxidative stress resistance and drive RCC progression. Targeting mitochondrial proteins lactylation, exemplified by MDH2 K239la , represents a promising therapeutic strategy for RCC.
研究领域:
癌症生物学
·
生物化学
·
细胞生物学
·
分子生物学
·
代谢工程
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2024
·
IF 4
Wei Liu,Sufei Zhou,Ke Yang,Di Liu,Yuxing Yan,Fangzhen Tian,Tianyi Cui,Wei Wang,Lewei Bi,Lan Li,Hao Wang,Xiao-Dong Zhang
Currently, pulmonary complications such as lung infections during the perioperative period are still the main cause of prolonged hospitalization and death in patients with lung injury due to the lack of effective drugs. Clusterzyme, a kind of artificial enzyme with a high enzyme-like activity and safety profile, exhibits good effects on reducing oxidative stress and immunomodulation. Here, we present the functionalized patches that is administered on the lung airways and rescues the injured organ via clusterzymes. The long-term antioxidant capacity of the patches significantly ameliorated lipopolysaccharide-induced lung function impairment with a significant reduction in lung goblet cell metaplasia and oxidative stress. The inflammatory factors such as cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α levels decreased by 50%, while the mtDNA copy number increased by 50% and ATP production increased by 100%. Mice lung function was significantly improved, suggesting that the patches can rescue lung injury by modulating oxidative stress and immune responses as well as protecting the mitochondria, providing an avenue for effective intervention of lung injury.
研究领域:
药理学
·
免疫学
·
呼吸医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Kunlong Yang,Yue Luo,Tongzheng Sun,Han Qiu,Qingru Geng,Yongxin Li,Man Liu,Nancy P. Keller,Fengqin Song,Jun Tian
Nitric oxide (NO) is a signaling molecule with diverse roles in various organisms. However, its role in the opportunistic pathogen Aspergillus flavus remains unclear. This study investigates the potential of NO, mediated by metabolites from A. oryzae (AO), as an antifungal strategy against A . flavus . We demonstrated that AO metabolites effectively suppressed A . flavus asexual development, a critical stage in its lifecycle. Transcriptomic analysis revealed that AO metabolites induced NO synthesis genes, leading to increased intracellular NO levels. Reducing intracellular NO content rescued A . flavus spores from germination inhibition caused by AO metabolites. Furthermore, exogenous NO treatment and dysfunction of flavohemoglobin Fhb1, a key NO detoxification enzyme, significantly impaired A . flavus asexual development. RNA-sequencing and metabolomic analyses revealed significant metabolic disruptions within tricarboxylic acid (TCA) cycle upon AO treatment. NO treatment significantly reduced mitochondrial membrane potential (Δψm) and ATP generation. Additionally, aberrant metabolic flux within the TCA cycle was observed upon NO treatment. Further analysis revealed that NO induced S-nitrosylation of five key TCA cycle enzymes. Genetic analysis demonstrated that the S-nitrosylated Aconitase Acon and one subunit of succinate dehydrogenase Sdh2 played crucial roles in A . flavus development by regulating ATP production. This study highlights the potential of NO as a novel antifungal strategy to control A . flavus by compromising its mitochondrial function and energy metabolism.
研究领域:
微生物学
·
分子生物学
·
真菌学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2023
·
IF 3.9
Peng Hui- xin,Chai Fu,Chen Ke-heng,Huang Yan-xin,Wei Guang-ji,Yuan Huixiong,Pang Yan-fang,Luo Shi-hua,Wang Chun-fang,Chen Wen-cheng
Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl 3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl 3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl 3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl 3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl 3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl 3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl 3 exposure and offer a foundation for future research in this area.
研究领域:
毒理学
·
生殖生物学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-13
·
IF 4.259
Chen Xubo,Zhao Xueyan,Lan Fazhang,Zhou Tao,Cai Hua,Sun Haiying,Kong Weijia,Kong Wen
Studies have reported attenuation of insulin resistance (IR) by improving phosphorylation of the insulin signalling pathway. However, the upstream molecular signalling pathway is still elusive. In this study, Western blot was used to evaluate the phosphorylation level of the insulin signalling pathway and the AMPK pathway. 2-NBDG was used to evaluate glucose uptake. Ca 2+ imaging was used to assess change of intracellular Ca 2+ concentration. We found that NaHS enhanced the intracellular Ca 2+ concentration and glucose uptake and activated the insulin signalling cascade in a palmitic acid (PA)-induced IR model in C2C12 cells. Furthermore, activation of the IRS1/PI3K/AKT pathway and glucose uptake were decreased when AMPK or CaMKKβ was inhibited. Our study also showed that the mitochondrial electron transport chain, ATP production, and intramitochondrial cAMP declined in the IR model but that this effect was reversed by NaHS, an effect that may be mediated by the Ca 2+ /CaMKK2/AMPK and PI3K/AKT pathways. Our data indicate that H 2 S improves activation of the insulin signalling cascade and glucose uptake via activation of the Ca 2+ /CaMKK2/AMPK pathway and mitochondrial metabolism in C2C12 cells. Furthermore, NaHS protects mitochondrial function and maintains normal ATP production by activating the cAMP system and the Ca 2+ /CaMKK2/AMPK and PI3K/ATK pathways.
研究领域:
分子生物学
·
细胞代谢
·
内分泌学
·
糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2022
·
IF 6.796
Ruohua Qu,Mi Chen,Jingfu Liu,Qiting Xie,Na Liu,Fei Ge
Adenosine triphosphate (ATP) generation of aquatic organisms is often subject to nanoparticles (NPs) stress, involving extensive reprogramming of gene expression and changes in enzyme activity accompanied by metabolic disturbances. However, little is known about the mechanism of energy supply by ATP to regulate the metabolism of aquatic organisms under NPs stress. Here, we selected extensively existing silver nanoparticles (AgNPs) to investigate their implications on ATP generation and relevant metabolic pathways in alga ( Chlorella vulgaris ). Results showed that ATP content significantly decreased by 94.2% of the control (without AgNPs) in the algal cells at 0.20 mg/L AgNPs, which was mainly attributed to the reduction of chloroplast ATPase activity (81.4%) and the downregulation of ATPase-coding genes atp B and atp H (74.5%-82.8%) in chloroplast. Molecular dynamics simulations demonstrated that AgNPs competed with the binding sites of substrates adenosine diphosphate and inorganic phosphate by forming a stable complex with ATPase subunit beta, potentially resulting in the reduced binding efficiency of substrates. Furthermore, metabolomics analysis proved that the ATP content positively correlated with the content of most differential metabolites such as D-talose, myo-inositol, and L-allothreonine. AgNPs remarkably inhibited ATP-involving metabolic pathways, including inositol phosphate metabolism, phosphatidylinositol signaling system, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and glutathione metabolism. These results could provide a deep understanding of energy supply in regulating metabolic disturbances under NPs stress.
研究领域:
环境科学
·
分子生物学
·
生物化学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NPG Asia Materials
·
2019
·Vol. 11
·期 1
·1-18
·
IF 8.052
Liang Jianming,Zhu Ying,Gao Caifang,Ling Chengli,Qin Jing,Wang Qi,Huang Yongzhuo,Lu Weigen,Wang Jianxin
Current chemotherapeutics for glioma are not sufficiently effective due to their low tolerance and poor blood–brain barrier (BBB) permeability. Energy restriction based on co-delivery of albendazole (Abz) and nano-silver has been proven to suppress tumor growth without adverse effects. Accordingly, menthol was conjugated to BSA (MeB) to overcome the BBB-permeability issue. In this study, Abz-loaded MeB-silver nanoparticles (MBS-Abz) were developed by self-assembly of MeB, albendazole and nano silver for glioma targeting therapy. The nanoparticle entered the brain across the BBB and specifically accumulated in the glioma region. MeB delivered the nanoparticles across the brain capillary endothelial cell monolayer by promoting internalization and BBB disruption. MBS-Abz hindered ATP generation via the inhibition of glycolytic and mitochondrial pathways both in vitro and in vivo. The anti-glioma mechanisms of energy restriction were related to the cytotoxicity, proliferation inhibition, cell cycle arrest, and apoptosis induced by ATP exhaustion, and the effects of MBS-Abz were significantly better than those induced by monotherapy nanoparticles or unmodified nanoparticles. These results demonstrated that by combining the energy restriction effect of albendazole and nano silver, as well as the BBB penetration ability of menthol, MBS-Abz achieves superior anti-glioma efficacy and can be an effective strategy for glioma therapy.
研究领域:
药理学
·
神经科学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
iMeta
·
2024
·
IF 23.7
Hao Zhang,Jiawan Wang,Jianghua Shen,Siqi Chen,Hailong Yuan,Xuan Zhang,Xu Liu,Ying Yu,Xinran Li,Zeyu Gao,Yaohui Wang,Jun Wang,Moshi Song
Emerging evidence has demonstrated the profound impact of the gut microbiome on cardiovascular diseases through the production of diverse metabolites. Using an animal model of myocardial ischemia–reperfusion (I/R) injury, we found that the prophylactic administration of a well-known probiotic, Bifidobacterium infantis ( B. infantis ), exhibited cardioprotective effects in terms of preserving cardiac contractile function and preventing adverse cardiac remodeling following I/R and that these cardioprotective effects were recapitulated by its metabolite inosine. Transcriptomic analysis further revealed that inosine mitigated I/R-induced cardiac inflammation and cell death. Mechanistic investigations elucidated that inosine suppressed the production of pro-inflammatory cytokines and reduced the numbers of dendritic cells and natural killer cells, achieved through the activation of the adenosine A2A receptor (A2AR) that when inhibited abrogated the cardioprotective effects of inosine. Additionally, in vitro studies using C2C12 myoblasts revealed that inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate (ATP) generation through the purine salvage pathway when subjected to oxygen-glucose deprivation/reoxygenation that simulated myocardial I/R injury. Likewise, inosine reversed the I/R-induced decrease in ATP levels in mouse hearts. Taken together, our findings indicate that B. infantis or its metabolite inosine exerts cardioprotective effects against I/R by suppressing cardiac inflammation and attenuating cardiac cell death, suggesting prophylactic therapeutic options for acute ischemic cardiac injury. Graphical In this study, we found that the prophylactic administration of a well-known probiotic, Bifidobacterium infantis ( B. infantis ), exhibited cardioprotective effects against myocardial ischemia–reperfusion (I/R) injury, which was recapitulated by its metabolite inosine. Specifically, inosine suppressed cardiac inflammation by reducing the production of pro-inflammatory cytokines and decreasing the numbers of dendritic cells and natural killer cells after I/R. Additionally, inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate generation through the purine salvage pathway in stressed myocytes and in I/R-injured mouse hearts. Collectively, our findings indicate that B. infantis or its metabolite inosine exerts pleiotropic cardioprotective effects against I/R, suggesting prophylactic therapeutic options for acute ischemic cardiac injury. Highlights Bifidobacterium infantis , a well-known probiotic, exhibits prophylactic cardioprotective effects against myocardial I/R injury. The cardioprotective effects of Bifidobacterium infantis are recapitulated by its metabolite inosine. Inosine treatment suppresses cardiac inflammation by reducing the production of pro-inflammatory cytokines and decreasing the numbers of dendritic cells and natural killer cells after I/R. Inosine treatment attenuates cell death by serving as an alternative carbon source for adenosine triphosphate generation through the purine salvage pathway in stressed myocytes and in I/R-injured mouse hearts.
研究领域:
心血管疾病
·
微生物组
·
免疫学
·
代谢组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）