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Acta Biochimica Polonica 2024Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in... (Review)
Review
Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in new functional areas such as cytoprotection, cellular senescence, tumor function and inflammation. The basis of these new areas still relies on fundamental biochemical/biophysical mitochondrial functions such as synthesis of reactive oxygen species, mitochondrial membrane potential, and the integrity of the inner mitochondrial membrane i.e., the passage of various molecules through the mitochondrial membranes. In this view transport of potassium cations, known as the potassium cycle, plays an important role. It is believed that K influx is mediated by various potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of the key findings and characteristics of mitochondrial potassium channels derived from research of many groups conducted over the past 33 years. We propose a list of six fundamental observations and most important ideas dealing with mitochondrial potassium channels. We also discuss the contemporary challenges and future prospects associated with research on mitochondrial potassium channels.
Topics: Humans; Mitochondria; Potassium Channels; Animals; Potassium; Mitochondrial Membranes; Membrane Potential, Mitochondrial; Reactive Oxygen Species
PubMed: 38863652
DOI: 10.3389/abp.2024.13126 -
MBio Jun 2024Sepsis and chronic infections with , a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The...
UNLABELLED
Sepsis and chronic infections with , a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine infection we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.
IMPORTANCE
Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.
PubMed: 38860823
DOI: 10.1128/mbio.01292-24 -
Nature Communications Jun 2024The development of Type I photosensitizers (PSs) is of great importance due to the inherent hypoxic intolerance of photodynamic therapy (PDT) in the hypoxic...
The development of Type I photosensitizers (PSs) is of great importance due to the inherent hypoxic intolerance of photodynamic therapy (PDT) in the hypoxic microenvironment. Compared to Type II PSs, Type I PSs are less reported due to the absence of a general molecular design strategy. Herein, we report that the combination of typical Type II PS and natural substrate carvacrol (CA) can significantly facilitate the Type I pathway to efficiently generate superoxide radical (O). Detailed mechanism study suggests that CA is activated into thymoquinone (TQ) by local singlet oxygen generated from the PS upon light irradiation. With TQ as an efficient electron transfer mediator, it promotes the conversion of O to O by PS via electron transfer-based Type I pathway. Notably, three classical Type II PSs are employed to demonstrate the universality of the proposed approach. The Type I PDT against S. aureus has been demonstrated under hypoxic conditions in vitro. Furthermore, this coupled photodynamic agent exhibits significant bactericidal activity with an antibacterial rate of 99.6% for the bacterial-infection female mice in the in vivo experiments. Here, we show a simple, effective, and universal method to endow traditional Type II PSs with hypoxic tolerance.
Topics: Benzoquinones; Photosensitizing Agents; Animals; Mice; Female; Photochemotherapy; Electron Transport; Staphylococcus aureus; Cymenes; Anti-Bacterial Agents; Singlet Oxygen; Superoxides; Staphylococcal Infections; Humans; Light; Mice, Inbred BALB C
PubMed: 38858372
DOI: 10.1038/s41467-024-49311-z -
Translational Andrology and Urology May 2024
PubMed: 38855601
DOI: 10.21037/tau-23-602 -
Oxidative Medicine and Cellular... 2024The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 is critical in preventing neurotoxicity caused by...
The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 is critical in preventing neurotoxicity caused by N-methyl-D-aspartate receptor activation (NMDARs). The activity of NMDARs places demands on endogenous cannabinoids to regulate their calcium currents. Endocannabinoids keep NMDAR activity within safe limits, protecting neural cells from excitotoxicity. Cannabinoids are remembered to deliver this outcome by repressing presynaptic glutamate discharge or obstructing postsynaptic NMDAR-managed flagging pathways. The endocannabinoid system must exert a negative influence proportional to the strength of NMDAR signaling for such control to be effective. The goal of this paper is to draw the attention towards the neuroprotective mechanism of constituents of against NMDA-induced excitotoxic result. Phytochemical investigation of the cannabis flowers led to the isolation of nine secondary metabolites. A spiro-compound, Cannabispirenone A, which on treatment of the cells prior to NMDA exposure significantly increases cell survival while decreasing ROS production, lipid peroxidation, and intracellular calcium. Our findings showed that this compound showed neuroprotection against NMDA-induced excitotoxic insult, has antioxidative properties, and increased cannabinoid receptor 1 expression, which may be involved in the signaling pathway for this neuroprotection.
Topics: Neuroprotective Agents; Animals; N-Methylaspartate; Mice; Cell Differentiation; Calcium; Receptors, N-Methyl-D-Aspartate; Reactive Oxygen Species; Cell Survival; Cannabis
PubMed: 38855429
DOI: 10.1155/2024/3530499 -
Research Square May 20243D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here we dissect the distinct cell fitness in 2D...
3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFβ-SMAD specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (, , and ) has opposite outcomes in 2D vs. 3D. We further identify a 3D-dependent synthetic lethality with partial loss of due to a reduction of expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic and organogenesis signaling dependencies under different cellular settings.
PubMed: 38853928
DOI: 10.21203/rs.3.rs-4390765/v1 -
Scientific Reports Jun 2024Water eutrophication has emerged as a pressing concern for massive algal blooms, and these harmful blooms can potentially generate harmful toxins, which can...
Water eutrophication has emerged as a pressing concern for massive algal blooms, and these harmful blooms can potentially generate harmful toxins, which can detrimentally impact the aquatic environment and human health. Consequently, it is imperative to identify a safe and efficient approach to combat algal blooms to safeguard the ecological safety of water. This study aimed to investigate the procedure for extracting total flavonoids from Z. bungeanum residue and assess its antioxidant properties. The most favorable parameters for extracting total flavonoids from Z. bungeanum residue were a liquid-solid ratio (LSR) of 20 mL/g, a solvent concentration of 60%, an extraction period of 55 min, and an ultrasonic temperature of 80 °C. Meanwhile, the photosynthetic inhibitory mechanism of Z. bungeanum residue extracts against M. aeruginosa was assessed with a particular focus on the concentration-dependent toxicity effect. Z. bungeanum residue extracts damaged the oxygen-evolving complex structure, influenced energy capture and distribution, and inhibited the electron transport of PSII in M. aeruginosa. Furthermore, the enhanced capacity for ROS detoxification enables treated cells to sustain their photosynthetic activity. The findings of this study hold considerable relevance for the ecological management community and offer potential avenues for the practical utilization of resources in controlling algal blooms.
Topics: Microcystis; Flavonoids; Photosynthesis; Zanthoxylum; Plant Extracts; Antioxidants; Allelopathy; Harmful Algal Bloom; Reactive Oxygen Species; Photosystem II Protein Complex
PubMed: 38851826
DOI: 10.1038/s41598-024-64129-x -
Journal of Dairy Science Jun 2024Hepatocellular lipid accumulation characterizes fatty liver in dairy cows. Lipid droplets (LD), specialized organelles that store lipids and maintain cellular lipid...
Hepatocellular lipid accumulation characterizes fatty liver in dairy cows. Lipid droplets (LD), specialized organelles that store lipids and maintain cellular lipid homeostasis, are responsible for the ectopic storage of lipids associated with several metabolic disorders. In recent years, non-ruminant studies have reported that LD-mitochondria interactions play an important role in lipid metabolism. Due to the role of diacylglycerol acyltransferase isoforms (DGAT1 and DGAT2) in LD synthesis, we explored mechanisms of mitochondrial fatty acid transport in ketotic cows using liver biopsies and isolated primary hepatocytes. Compared with healthy cows, cows with fatty liver had massive accumulation of LD and high protein expression of the triglyceride (TAG) synthesis-related enzymes DGAT1 and DGAT2, LD synthesis-related proteins perilipin 2 (PLIN2) and perilipin 5 (PLIN5), and the mitochondrial fragmentation-related proteins dynamin-related protein 1 (DRP1) and fission 1 (FIS1). In contrast, factors associated with fatty acid oxidation, mitochondrial fusion and mitochondrial electron transport chain complex were lower compared with those in the healthy cows. In addition, transmission electron microscopy revealed significant contacts between LD-mitochondria in liver tissue from cows with fatty liver. Compared with isolated cytoplasmic mitochondria, expression of carnitine palmitoyl transferase 1A (CPT1A) and DRP1 was lower, but mitofusin 2 (MFN2) and mitochondrial electron transport chain complex was greater in isolated peridroplet mitochondria from hepatic tissue of cows with fatty liver. In vitro data indicated that exogenous free fatty acids (FFA) induced hepatocyte LD synthesis and mitochondrial dynamics consistent with in vivo results. Furthermore, DGAT2 inhibitor treatment attenuated the FFA-induced upregulation of PLIN2 and PLIN5 and rescued the impairment of mitochondrial dynamics. Inhibition of DGAT2 also restored mitochondrial membrane potential and reduced hepatocyte reactive oxygen species production. The present in vivo and in vitro results indicated there are functional differences among different types of mitochondria in the liver tissue of dairy cows with ketosis. Activity of DGAT2 may play a key role in maintaining liver mitochondrial function and lipid homeostasis in dairy cows during the transition period.
PubMed: 38851581
DOI: 10.3168/jds.2024-24738 -
Biomedicine & Pharmacotherapy =... Jul 2024Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can...
Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can inhibit tumor growth by participating in ferroptosis remains unconfirmed. In this study, we demonstrated that berberine synergistically inhibited NSCLC in combination with multiple ferroptosis inducers, and this combination synergistically down-regulated the mRNA and protein expression of SLC7A11, GPX4, and NRF2, resulting in ferroptosis accompanied by significant depletion of GSH, and aberrant accumulation of reactive oxygen species and malondialdehyde. In a lung cancer allograft model, the combination treatment exhibited enhanced anticancer effects compared to using either drug alone. Notably, p53 is critical in determining the ferroptosis sensitivity. We found that the combination treatment did not elicit a synergistic anticancer effect in cells with a p53 mutation or with exogenous expression of mutant p53. These findings provide insight into the mechanism by which combination induces ferroptosis and the regulatory role of p53 in this process. It may guide the development of new strategies for treating NSCLC, offering great medical potential for personal diagnosis and treatment.
Topics: Ferroptosis; Berberine; Carcinoma, Non-Small-Cell Lung; Tumor Suppressor Protein p53; Humans; Phospholipid Hydroperoxide Glutathione Peroxidase; Lung Neoplasms; Amino Acid Transport System y+; Drug Synergism; Animals; Signal Transduction; Cell Line, Tumor; Reactive Oxygen Species; Mice; Mice, Nude; Mice, Inbred BALB C; NF-E2-Related Factor 2; A549 Cells
PubMed: 38850659
DOI: 10.1016/j.biopha.2024.116832 -
Breast Cancer Research : BCR Jun 2024Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to...
BACKGROUND
Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression.
METHODS
We used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity.
RESULTS
PC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors.
CONCLUSIONS
We present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.
Topics: Pyruvate Carboxylase; Animals; Female; Mice; Humans; Breast Neoplasms; Cell Line, Tumor; Lactic Acid; Gene Expression Regulation, Neoplastic; Cell Hypoxia; Lung Neoplasms; Immune Tolerance
PubMed: 38849928
DOI: 10.1186/s13058-024-01854-1