The neurotoxicity of phosphorylated tau protein (P-tau) and mitochondrial dysfunction play a significant role in the pathophysiology of Alzheimer's disease (AD). In vitro studies of the effects of P-tau oligomers on mitochondrial bioenergetics and reactive oxygen species production will allow us to evaluate the direct influence of P-tau on mitochondrial function. We measured the in vitro effect of P-tau oligomers on oxygen consumption and hydrogen peroxide production in isolated brain mitochondria. An appropriate combination of specific substrates and inhibitors of the phosphorylation pathway enabled the measurement and functional analysis of the effect of P-tau on mitochondrial respiration in defined coupling control states achieved in complex I-, II-, and I&II-linked electron transfer pathways. At submicromolar P-tau concentrations, we found no significant effect of P-tau on either mitochondrial respiration or hydrogen peroxide production in different respiratory states. The titration of P-tau showed a nonsignificant dose-dependent decrease in hydrogen peroxide production for complex I- and I&II-linked pathways. An insignificant in vitro effect of P-tau oligomers on both mitochondrial respiration and hydrogen peroxide production indicates that P-tau-induced mitochondrial dysfunction in AD is not due to direct effects of P-tau on the efficiency of the electron transport chain and on the production of reactive oxygen species.
- MeSH
- Cell Respiration MeSH
- Phosphorylation MeSH
- Rats MeSH
- Humans MeSH
- Mitochondria * metabolism MeSH
- Brain metabolism MeSH
- Hydrogen Peroxide * metabolism MeSH
- tau Proteins * metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Oxygen Consumption MeSH
- Electron Transport MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
- MeSH
- Electrons MeSH
- Fumarates metabolism MeSH
- Hypoxia metabolism MeSH
- Oxygen metabolism MeSH
- Humans MeSH
- Mitochondria * metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Succinate Dehydrogenase metabolism MeSH
- Electron Transport MeSH
- Ubiquinone * metabolism analogs & derivatives MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The unique potential of fullerene C60 for various biological applications has ignited significant interest. However, its inherent non-polarity poses a critical challenge for its effective integration within biological systems. This study delves into the intricate physicochemical characteristics of the innovative [C60 + NO] complex using density functional theory and time-dependent density functional theory. The computational analyses encompass molecular charge, surface electrostatic potential, and dipole moment evaluations. Impressively, the dipole moment of the [C60 + NO] complex significantly increases to 12.92 D. Meticulous surface analysis reveals a subtle interplay between molecular structures, indicating weak interactions. The analysis of the absorption spectrum unveils a noteworthy red-shift of 200 nm subsequent to complex formation. To elucidate the electron transfer mechanisms, we explore photo-induced electron transfer through CAM-B3LYP. This exploration elucidates intricate pathways governing electron transfer, with complementary insights gleaned from Marcus theory's outputs, especially the Gibbs free energy of electron transfer. Changes in the physicochemical properties of approaching C60 and NO molecules reveal interesting results compared to separate molecules. These findings resonate profoundly in the context of potential biological and pharmaceutical utilization. With implications for the biomedical area, the outcomes linked to the [C60 + NO] complex kindle optimism for pioneering biomedical applications.
- MeSH
- Fullerenes * chemistry MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Nitric Oxide MeSH
- Electron Transport MeSH
- Publication type
- Journal Article MeSH
Electrochemical methods can be used not only for the sensitive analysis of proteins but also for deeper research into their structure, transport functions (transfer of electrons and protons), and sensing their interactions with soft and solid surfaces. Last but not least, electrochemical tools are useful for investigating the effect of an electric field on protein structure, the direct application of electrochemical methods for controlling protein function, or the micromanipulation of supramolecular protein structures. There are many experimental arrangements (modalities), from the classic configuration that works with an electrochemical cell to miniaturized electrochemical sensors and microchip platforms. The support of computational chemistry methods which appropriately complement the interpretation framework of experimental results is also important. This text describes recent directions in electrochemical methods for the determination of proteins and briefly summarizes available methodologies for the selective labeling of proteins using redox-active probes. Attention is also paid to the theoretical aspects of electron transport and the effect of an external electric field on the structure of selected proteins. Instead of providing a comprehensive overview, we aim to highlight areas of interest that have not been summarized recently, but, at the same time, represent current trends in the field.
Biochemické děje jako fotosyntéza a respirace, při nichž dochází k redoxním reakcím a přenosu elektronů pomocí kaskád proteinových molekul, souhrnně je označujeme jako elektron‐transportní systémy, jsou pro život na Zemi klíčové a nezbytné. Vhodným modelovým proteinem pro studium strukturně funkčních vztahů elektron‐transportních systémů proteinové povahy a vlivu aminokyselinových zbytků či záměny centrálního kovu na redox procesy je azurin, který patří do rodiny malých rozpustných cupredoxinů a podílí se na přenosu elektronů při anaerobní respiraci bakterií rodu Pseudomonas.
Biochemical processes like photosynthesis and cellular respiration, which involve redox reactions and are facilitated by electron transfer through a cascade of protein molecules, commonly referred to as electron‐transfer systems, play a key role in all life on Earth. Azurin is a suitable model to study structural properties of such electron‐transfer systems and the role of individual amino acid residues or the central metal ion in redox reactions. This protein belongs to the family of small soluble electron transporters known as cupredoxines and has a physiological role during anaerobic respiration in Pseudomonas bacterial species.
- Keywords
- cupredoxiny,
- MeSH
- Azurin * chemistry MeSH
- Electron Transport MeSH
Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson ́s disease, Huntington ́s disease, Alzheimer ́s disease, amyotrophic lateral sclerosis, Friedreich ́s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson ́s disease) or rather vague (e.g. Friedreich ́s ataxia or amyotrophic lateral sclerosis).
- MeSH
- Antioxidants pharmacology MeSH
- Humans MeSH
- Mitochondrial Diseases * metabolism MeSH
- Mitochondria metabolism MeSH
- Nervous System Diseases * drug therapy metabolism MeSH
- Electron Transport MeSH
- Ubiquinone analogs & derivatives therapeutic use MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Histone deacylase 11 and human sirtuins are able to remove fatty acid-derived acyl moieties from the ε-amino group of lysine residues. Specific substrates are needed for investigating the biological functions of these enzymes. Additionally, appropriate screening systems are required for identification of modulators of enzymatic activities of HDAC11 and sirtuins. We designed and synthesized a set of activity probes by incorporation of a thioamide quencher unit into the fatty acid-derived acyl chain and a fluorophore in the peptide sequence. Systematic variation of both fluorophore and quencher position resulted "super-substrates" with catalytic constants of up to 15,000,000 M-1s-1 for human sirtuin 2 (Sirt2) enabling measurements using enzyme concentrations down to 100 pM in microtiter plate-based screening formats. It could be demonstrated that the stalled intermediate formed by the reaction of Sirt2-bound thiomyristoylated peptide and NAD+ has IC50 values below 200 pM.
- MeSH
- Fluorescent Dyes chemistry pharmacology MeSH
- Photochemical Processes MeSH
- Histone Deacetylases chemistry genetics metabolism MeSH
- Humans MeSH
- Molecular Structure MeSH
- Positron-Emission Tomography * MeSH
- Sirtuins antagonists & inhibitors chemistry metabolism MeSH
- Thioamides chemistry pharmacology MeSH
- Electron Transport MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Three-dimensional (3D) printing technology offers attractive possibilities for many fields. In electrochemistry, 3D printing technology has been used to fabricate customized 3D-printed electrodes as a platform to develop bio/sensing, energy generation and storage devices. Here, we use a 3D-printed graphene/polylactic (PLA) electrode made by additive manufacturing technology and immobilize horseradish peroxidase (HRP) to create a direct electron transfer enzyme-based biosensors for hydrogen peroxide detection. Gold nanoparticles are included in the system to confirm and facilitate heterogeneous electron transfer. This work opens a new direction for the fabrication of third-generation electrochemical biosensors using 3D printing technology, with implications for applications in the environmental and biomedical fields.
Mitochondrial disorders manifest enormous genetic and clinical heterogeneity - they can appear at any age, present with various phenotypes affecting any organ, and display any mode of inheritance. What mitochondrial diseases do have in common, is impairment of respiratory chain activity, which is responsible for more than 90% of energy production within cells. While diagnostics of mitochondrial disorders has been accelerated by introducing Next-Generation Sequencing techniques in recent years, the treatment options are still very limited. For many patients only a supportive or symptomatic therapy is available at the moment. However, decades of basic and preclinical research have uncovered potential target points and numerous compounds or interventions are now subjects of clinical trials. In this review, we focus on current and emerging therapeutic approaches towards the treatment of mitochondrial disorders. We focus on small compounds, metabolic interference, such as endurance training or ketogenic diet and also on genomic approaches.
- MeSH
- Genetic Therapy methods MeSH
- Humans MeSH
- Mitochondrial Diseases genetics metabolism therapy MeSH
- Mitochondria metabolism pathology MeSH
- Electron Transport MeSH
- High-Throughput Nucleotide Sequencing methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Many biochemical reactions are based on redox reactions. Therefore, the redox potential of a chemical compound may be related to its therapeutic or physiological effects. The study of redox properties of compounds is a domain of electrochemistry. The subject of this review is the relationship between electrochemistry and medicinal chemistry, with a focus on quantifying these relationships. A summary of the relevant achievements in the correlation between redox potential and structure, therapeutic activity, resp., is presented. The first part of the review examines the applicability of QSPR for the prediction of redox properties of medically important compounds. The second part brings the exhaustive review of publications using redox potential as a molecular descriptor in QSAR of biological activity. Despite the complexity of medicinal chemistry and biological reactions, it is possible to employ redox potential in QSAR/QSPR. In many cases, this electrochemical parameter plays an essential but rarely absolute role.
- MeSH
- Anti-Bacterial Agents chemistry MeSH
- Antioxidants chemistry MeSH
- Antiprotozoal Agents chemistry MeSH
- Antiviral Agents chemistry MeSH
- Chemistry, Pharmaceutical * MeSH
- Quantitative Structure-Activity Relationship * MeSH
- Oxidation-Reduction MeSH
- Antineoplastic Agents chemistry MeSH
- Electron Transport MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
