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OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore.
No full textThe permeability transition pore (PTP) is a latent, high-conductance channel of the inner mitochondrial membrane. When
activated, it plays a key role in cell death and therefore in several diseases. The investigation of the PTP took an unexpected turn
after the discovery that cyclophilin D (the target of the PTP inhibitory effect of cyclosporin A) binds to FOF1 (F)-ATP synthase, thus
inhibiting its catalytic activity by about 30%. This observation was followed by the demonstration that binding occurs at a
particular subunit of the enzyme, the oligomycin sensitivity conferral protein (OSCP), and that F-ATP synthase can form
Ca2+-activated, high-conductance channels with features matching those of the PTP, suggesting that the latter originates from a
conformational change in F-ATP synthase. This review is specifically focused on the OSCP subunit of F-ATP synthase, whose
unique features make it a potential pharmacological target both for modulation of F-ATP synthase and its transition to a pore
The mitochondrial permeability transition: Recent progress and open questions
Full text linkMajor progress has been made in defining the basis of the mitochondrial permeability transition, a Ca2+-dependent permeability increase of the inner membrane that has puzzled mitochondrial research for almost 70 years. Initially considered an artefact of limited biological interest by most, over the years the permeability transition has raised to the status of regulator of mitochondrial ion homeostasis and of druggable effector mechanism of cell death. The permeability transition is mediated by opening of channel(s) modulated by matrix cyclophilin D, the permeability transition pore(s) (PTP). The field has received new impulse (a) from the hypothesis that the PTP may originate from a Ca2+-dependent conformational change of F-ATP synthase and (b) from the reevaluation of the long-standing hypothesis that it originates from the adenine nucleotide translocator (ANT). Here, we provide a synthetic account of the structure of ANT and F-ATP synthase to discuss potential and controversial mechanisms through which they may form high-conductance channels; and review some intriguing findings from the wealth of early studies of PTP modulation that still await an explanation. We hope that this review will stimulate new experiments addressing the many outstanding problems, and thus contribute to the eventual solution of the puzzle of the permeability transition
ATP synthase complex from beef heart mitochondria: role of the thiol group of the 25 kDa subunit of the F0 in the coupling mechanism between F0 and F1
No full textn order to assess the role of thiol groups in the Fo part of the ATP synthase in the coupling mechanism of ATP synthase, we have treated isolated Fo, extracted from beef heart Complex V with urea, with thiol reagents, primarily with diazenedicarboxylic acid bis-(dimethylamide) (diamide) but also with Cd2+ and N-ethylmaleimide. FoF1 ATP synthase was reconstituted by adding isolated F1 and the oligomycin-sensitivity-conferring-protein (OSCP) to Fo. The efficiency of reconstitution was assessed by determining the sensitivity to oligomycin of the ATP hydrolytic activity of the reconstituted enzyme. Contrary to Cd2+, incubation of diamide with Fo, before the addition of F1 and OSCP, induced a severe loss of oligomycin sensitivity, due to an inhibited binding of F1 to Fo. This effect was reversed by dithiothreitol. Conversely, if F1 and OSCP were added to Fo before diamide, no effect could be detected. These results show that F1 (and/or OSCP) protects Fo thiols from diamide and are substantiated by the finding that the oligomycin sensitivity of ATP hydrolysis activity of isolated Complex V was also unaltered by diamide. Gel electrophoresis of FoF1 ATP synthase, reconstituted with diamide-treated Fo, revealed that the loss of oligomycin sensitivity was directly correlated with diminution of band Fo 1 (or subunit b). Concomitantly a band appeared of approximately twice the molecular weight of subunit Fo 1. As this protein contains only 1 cysteine residue (Walker, J. E., Runswick, M. J., and Poulter, L. (1987) J. Mol. Biol. 197, 89-100), the effect of diamide is attributed to the formation of a disulfide bridge between two of these subunits. These results offer further evidence for the proposal, based on aminoacid sequence and structural analysis, that subunit Fo 1 of mammalian Fo is involved in the binding with F1 (Walker et al. (1987]. N-Ethylmaleimide affects oligomycin sensitivity to a lesser extent than diamide, suggesting that the mode of action of these reagents (and the structural changes induced in Fo) is different
The influence of the type of dry-cured Italian PDO ham on cathepsin B activity trend during processing
No full textCathepsin B activity was measured during processing in hams originating from the main Italian prosciutto PDOs: Parma, San Daniele and Toscano. Sixty-five heavy pig thighs, from sixty-five Italian large white x Italian Landrace pigs bred and slaughtered in the same conditions were considered. Five thighs represented the post-mortem control time. The other 60 were distributed one plant per PDO, following a balanced plan. The thighs were sampled at the biceps femoris in groups of four per plant in the following ripening phases: salting, resting, drying, greasing, end of curing. The activity of the Cathepsin B (U/g protein) was determined by means of fluorescence measurements. The Cathepsin B ripening trend of the various PDOs was significantly different, particularly during the initial and mid-curing stage. This activity correlates with the proteolysis index through a PDO dependent pattern, indicating that different processing conditions can influence the quality of prosciutto, since they determine its biochemical development
Functional fish: improving nutrition for the elderly
Full text linkElder people need highly digestible foods that can also provide health benefits even to those suffering from chronic diseases.
Furthermore, such foods should be palatable as well as familiar for elder consumers. Fish is a high-protein, low-fat food that
potentially provides a range of health promoting effects which may be further improved with suitable approaches in the
production systems. The present mini-review intends to report possible aquaculture interventions to enhance the positive
impact of fish on elder health and to promote its function in terms of prevention and recovery of specific diseases. Some fish
species during their lifespan experience periods of food restrictions that can be mimicked in aquaculture without affecting
fish welfare. Under these circumstances fish can modify the fatty acid profile and increase the use of muscle proteins to fulfill
their energy requirements, by activation of muscle endogenous proteases. Degradation of muscle proteins can enhance their
digestibility and possibly the release of encrypted bioactive peptides, showing a plethora of biological actions, including the
antihypertensive activity. The degree of myofibrillar protein degradation and the fatty acid profile of fish fillet can then be
managed by suitable and sustainable feeding protocols in the context of farming conditions
Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?
Full text linkMitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the “powerhouse of the cell” turns into the “factory of death” is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction with its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer’s Disease and Parkinson’s Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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