Journal of Bioenergetics and Biomembranes最新文献

Mitochondrial dysfunction plays a central role in Parkinson's disease (PD) and can be triggered by xenobiotics and mutations in mitochondrial quality control genes, such as the PINK1 gene. Caffeine has been proposed as a secondary treatment to relieve PD symptoms mainly by its antagonistic effects on adenosine receptors (ARs). Nonetheless, the potential protective effects of caffeine on mitochondrial dysfunction could be a strategy in PD treatment but need further investigation. In this study, we used high-resolution respirometry (HRR) to test caffeine's effects on mitochondrial dysfunction in PINK1^B9-null mutants of Drosophila melanogaster. PINK1 loss-of-function induced mitochondrial dysfunction in PINK1^B9-null flies observed by a decrease in O₂ flux related to oxidative phosphorylation (OXPHOS) and electron transfer system (ETS), respiratory control ratio (RCR) and ATP synthesis compared to control flies. Caffeine treatment improved OXPHOS and ETS in PINK^B9-null mutant flies, increasing the mitochondrial O₂ flux compared to untreated PINK^B9-null mutant flies. Moreover, caffeine treatment increased O₂ flux coupled to ATP synthesis and mitochondrial respiratory control ratio (RCR) in PINK 1^B9-null mutant flies. The effects of caffeine on respiratory parameters were abolished by rotenone co-treatment, suggesting that caffeine exerts its beneficial effects mainly by stimulating the mitochondrial complex I (CI). In conclusion, we demonstrate that caffeine may improve mitochondrial function by increasing mitochondrial OXPHOS and ETS respiration in the PD model using PINK1 loss-of-function mutant flies.

Background: Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production.

Aims: The aim of our study is to investigate the global status and trends of mitochondrial dynamics research and predict popular topics and directions in the field.

Methods: Publications related to the studies of mitochondrial dynamics from 2002 to 2021 were retrieved from Web of Science database. A total of 4,576 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software.

Results: There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model [Formula: see text]. The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA)-Molecular Cell Research had the largest publication numbers. Case Western Reserve University is the most contributive institution. The main research orientation and funding agency were cell biology and HHS. All keywords related studies could be divided into three clusters: "Related disease research", "Mechanism research" and "Cell metabolism research".

Conclusions: Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.

Myocardial ischemia-reperfusion (I/R) injury is a major cause of poor hemodynamic reconstitution outcomes after myocardial infarction or circulatory arrest. Currently, the search for effective therapeutic agents and tools is a focus of research in the field of myocardial I/R injury. Resveratrol (Res) has been extensively studied in recent years because of its good cardiovascular therapeutic effects, but its specific mechanism of action has not been fully elucidated. Therefore, the aim of this study was to investigate the mechanism of interaction between myocardial I/R injury and Res in vitro and in vivo. In our in vivo study, we used PI/TUNEL staining and western blotting to detect relevant necroptotic key molecules such as RIP1, RIP3 and p-MLKL/MLKL to observe myocardial necroptosis. The extent of myocardial injury was determined using hematoxylin and eosin (HE) staining and 2,3,5-triphenyltetrazolium chloride (TTC) staining as well as serum levels of CK-MB and LDH and echocardiography. In the in vitro study, cellular injury was assessed by CCK-8 and cell supernatant LDH levels. In addition, we used small interfering RNA (siRNA) transfection to knock down YAP, a key effector molecule of the Hippo pathway, to validate the molecular mechanism of action by which Res exerts myocardial protection. The localization of YAP in H9c2 cardiomyocytes was examined using immunofluorescence. Our data demonstrated that Res could ameliorate myocardial I/R-induced necroptosis by modulating the Hippo pathway, and that the beneficial effect of Res might be associated with nuclear translocation of the transcriptional regulator YAP.

The mitochondrial bc1 complex is a major source of mitochondrial superoxide. While bc1-generated superoxide plays a beneficial signaling role, excess production of superoxide lead to aging and degenerative diseases. The catalytic core of bc1 comprises three peptides -cytochrome b, Fe-S protein, and cytochrome c1. All three core peptides exhibit accelerated evolution in anthropoid primates. It has been suggested that the evolution of cytochrome b in anthropoids was driven by a pressure to reduce the production of superoxide. In humans, the bc1 core peptides exhibit anthropoid-specific substitutions that are clustered near functionally critical sites that may affect the production of superoxide. Here we compare the high-resolution structures of bovine, mouse, sheep and human bc1 to identify structural changes that are associated with human-specific substitutions. Several cytochrome b substitutions in humans alter its interactions with other subunits. Most significantly, there is a cluster of seven substitutions, in cytochrome b, the Fe-S protein, and cytochrome c1 that affect the interactions between these proteins at the tether arm of the Fe-S protein and may alter the rate of ubiquinone oxidation and the rate of superoxide production. Another cluster of substitutions near heme bH and the ubiquinone reduction site, Qi, may affect the rate of ubiquinone reduction and thus alter the rate of superoxide production. These results are compatible with the hypothesis that cytochrome b in humans (and other anthropoid primates) evolve to reduce the rate of production of superoxide thus enabling the exceptional longevity and exceptional cognitive ability of humans.

Exposure to the environmental pollutant lead (Pb) has been linked to Alzheimer's disease (AD), in which mitochondrial dysfunction is a pathological consequence of neuronal degeneration. The toxicity of Pb in combination with β-amyloid peptides (1-40) and (25-35) causes selective death in neuronal cells. However, the precise mechanism through which Pb induces Alzheimer's disease, particularly mitochondrial damage, is unknown. Changes in mitochondrial mass, membrane potential, mitochondrial complex activities, mitochondrial DNA and oxidative stress were examined in neuronal cells of human origin exposed to Pb and β-amyloid peptides (1-40) and (25-35) individually and in different combinations. The results showed depolarization of mitochondrial membrane potential, decrease in mitochondrial mass, ATP levels and mtDNA copy number in Pb and β-amyloid peptides (1-40) and (25-35) exposed cells. Also, significant reductions in the expression of mitochondrial electron transport chain (ETC) complex proteins (ATP5A, COXIV, UQCRC2, SDHB, NDUFS3), as well as down regulation of ETC complex gene expressions such as COXIV, ATP5F1 and NDUFS3 and antioxidant gene expressions like MnSOD and Gpx4 were observed in exposed cells. Furthermore, Pb and β-amyloid peptides exposure resulted in elevated mitochondrial malondialdehyde levels and a decrease in mitochondrial GSH levels. Our findings suggest that Pb toxicity could be one of the causative factors for the mitochondrial dysfunction and oxidative stress in Alzheimer's disease progression.

Salinibacter ruber is an extremophilic bacterium able to grow in high-salts environments, such as saltern crystallizer ponds. This halophilic bacterium is red-pigmented due to the production of several carotenoids and their derivatives. Two of these pigment molecules, salinixanthin and retinal, are reported to be essential cofactors of the xanthorhodopsin, a light-driven proton pump unique to this bacterium. Here, we isolate and characterize an outer membrane porin-like protein that retains salinixanthin. The characterization by mass spectrometry identified an unknown protein whose structure, predicted by AlphaFold, consists of a 8 strands beta-barrel transmembrane organization typical of porins. The protein is found to be part of a functional network clearly involved in the outer membrane trafficking. Cryo-EM micrographs showed the shape and dimensions of a particle comparable with the ones of the predicted structure. Functional implications, with respect to the high representativity of this protein in the outer membrane fraction, are discussed considering its possible role in primary functions such as the nutrients uptake and the homeostatic balance. Finally, also a possible involvement in balancing the charge perturbation associated with the xanthorhodopsin and ATP synthase activities is considered.

Propionic acid (PA) predominantly accumulates in tissues and biological fluids of patients affected by propionic acidemia that may manifest chronic renal failure along development. High urinary excretion of maleic acid (MA) has also been described. Considering that the underlying mechanisms of renal dysfunction in this disorder are poorly known, the present work investigated the effects of PA and MA (1-5 mM) on mitochondrial functions and cellular viability in rat kidney and cultured human embryonic kidney (HEK-293) cells. Mitochondrial membrane potential (∆ψm), NAD(P)H content, swelling and ATP production were measured in rat kidney mitochondrial preparations supported by glutamate or glutamate plus malate, in the presence or absence of Ca²⁺. MTT reduction and propidium iodide (PI) incorporation were also determined in intact renal cells pre-incubated with MA or PA for 24 h. MA decreased Δψm and NAD(P)H content and induced swelling in Ca²⁺-loaded mitochondria either respiring with glutamate or glutamate plus malate. Noteworthy, these alterations were fully prevented by cyclosporin A plus ADP, suggesting the involvement of mitochondrial permeability transition (mPT). MA also markedly inhibited ATP synthesis in kidney mitochondria using the same substrates, implying a strong bioenergetics impairment. In contrast, PA only caused milder changes in these parameters. Finally, MA decreased MTT reduction and increased PI incorporation in intact HEK-293 cells, indicating a possible association between mitochondrial dysfunction and cell death in an intact cell system. It is therefore presumed that the MA-induced disruption of mitochondrial functions involving mPT pore opening may be involved in the chronic renal failure occurring in propionic acidemia.

Circular RNAs (circRNAs) play vital roles in human diseases, including acute kidney injury (AKI). In this paper, we focused on the effect of circRNA zinc finger protein 644 (circZNF644) on AKI cell model progression. qRT-PCR was conducted for the levels of circZNF644, ZNF644, miR-140-5p and mixed lineage kinase domain like pseudokinase (MLKL). RNase R assay, actinomycin D assay and subcellular fraction analysis were conducted to analyze the features of circZNF644. CCK-8 assay and EdU assay were used to explore cell proliferation. Flow cytometry analysis was conducted to analyze cell cycle and cell apoptosis. Western blot assay was executed for protein levels. ELISA was performed for the levels of inflammatory cytokines. The relationships among circZNF644, miR-140-5p and MLKL were analyzed by dual-luciferase reporter assay and RIP assay. CircZNF644 was upregulated in LPS-stimulated HK-2 cells. LPS-mediated inhibitory effects on cell proliferation and cell cycle and promotional effects on apoptosis and inflammation were reversed by circZNF644 knockdown. CircZNF644 directly interacted with miR-140-5p and MLKL was the target gene of miR-140-5p. The impact of circZNF644 knockdown on HK-2 cell injury was relieved by miR-140-5p inhibition. Moreover, miR-140-5p enhancement alleviated LPS-triggered HK-2 cell damage, while MLKL elevation reversed the effect. CircZNF644 knockdown protected HK-2 cells from LPS-induced injury by altering miR-140-5p/MLKL pathway, suggesting that circZNF644 may be a hopeful therapeutic target for AKI.