Papers by Alessandra Pagliarani
Annals of the New York Academy of Sciences, 2019
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45° Congresso della Società Italiana di Biologia Marina, 2014
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Comparative Biochemistry and Physiology B, 2019
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… and Physiology Part C: …, 1996
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Biochimica et biophysica acta, Nov 1, 2017
The mitochondrial F1FO-ATPase has the main role in synthesizing most of ATP, thus providing energ... more The mitochondrial F1FO-ATPase has the main role in synthesizing most of ATP, thus providing energy to living cells, but it also works in reverse and hydrolyzes ATP, depending on the transmembrane electrochemical gradient. Within the same complex the vital role of the enzyme of life coexists with that of molecular switch to trigger programmed cell death. The two-faced vital/lethal role makes the enzyme complex an intriguing biochemical target to fight pathogens resistant to traditional therapies and diseases linked to mitochondrial dysfunctions. A variety of post-translational modifications (PTMs) of selected F1FO-ATPase aminoacids have been reported to affect the enzyme function. By reviewing the known PTMs of aminoacid side chains of both F1 and FO sectors according to the most recent advances, the main aim is to highlight how local chemical changes may constitute the molecular key leading to pathological or physiological events. PTMs represent the chemical tool to modulate the F1F...
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Science of The Total Environment, 2005
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Archives of Biochemistry and Biophysics
Phenylglyoxal (PGO), known to cause post-translational modifications of Arg residues, was used to... more Phenylglyoxal (PGO), known to cause post-translational modifications of Arg residues, was used to highlight the role of arginine residues of the F1FO-ATPase, which may be crucial to yield the mitochondrial permeability transition pore (mPTP). In swine heart mitochondria PGO inhibits ATP hydrolysis by the F1FO-ATPase either sustained by the natural cofactor Mg2+ or by Ca2+ by a similar uncompetitive inhibition mechanism, namely the tertiary complex (ESI) only forms when the ATP substrate is already bound to the enzyme, and with similar strength, as shown by the similar K'i values (0.82 ± 0.07 mM in presence of Mg2+ and 0.64 ± 0.05 mM in the presence of Ca2+). Multiple inhibitor analysis indicates that features of the F1 catalytic sites and/or the FO proton binding sites are apparently unaffected by PGO. However, PGO and F1 or FO inhibitors can bind the enzyme combine simultaneously. However they mutually hinder to bind the Mg2+-activated F1FO-ATPase, whereas they do not mutually exclude to bind the Ca2+-activated F1FO-ATPase. The putative formation of PGO-arginine adducts, and the consequent spatial rearrangement in the enzyme structure, inhibits the F1FO-ATPase activity but, as shown by the calcium retention capacity evaluation in intact mitochondria, apparently favours the mPTP formation.
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Trends in Cell Biology
The enzyme nicotinamide nucleotide transhydrogenase (NNT) transfers hydride from NADH to NADP+ co... more The enzyme nicotinamide nucleotide transhydrogenase (NNT) transfers hydride from NADH to NADP+ coupled to H+ translocation across the inner mitochondrial membrane. In a recent study, Kampjut and Sazanov reveal that the bifunctional NNT mechanism rules the NAD(P)+/NAD(P)H interconversion ratio, which in turn regulates antioxidant defense and sirtuin actions.
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Trends in Biochemical Sciences
As pointed out by Gu et al. (Science 2019) in mammalian mitochondria, the H-shaped tetrameric str... more As pointed out by Gu et al. (Science 2019) in mammalian mitochondria, the H-shaped tetrameric structure of the ATP synthase, the cell powerhouse, consists of two V-shaped dimers linked by two IF1 in antiparallel arrangement. This supramolecular structure reveals new functional/structural roles of the enzyme complex in mitochondria.
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SLAS DISCOVERY: Advancing the Science of Drug Discovery
Recently, the F1FO-ATP synthase, due to its dual role of life enzyme as main adenosine triphospha... more Recently, the F1FO-ATP synthase, due to its dual role of life enzyme as main adenosine triphosphate (ATP) maker and of death enzyme, as ATP dissipator and putative structural component of the mitochondrial permeability transition pore (mPTP), which triggers cell death, has been increasingly considered as a drug target. Accordingly, the enzyme offers new strategies to counteract the increased antibiotic resistance. The challenge is to find or synthesize compounds able to discriminate between prokaryotic and mitochondrial F1FO-ATP synthase, exploiting subtle structural differences to kill pathogens without affecting the host. From this perspective, the eukaryotic enzyme could also be made refractory to macrolide antibiotics by chemically produced posttranslational modifications. Moreover, because the mitochondrial F1FO-ATPase activity stimulated by Ca2+instead of by the natural modulator Mg2+is most likely involved in mPTP formation, effectors preferentially targeting the Ca2+-activat...
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Biochimie
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… and Physiology Part A: …, 1985
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Biochimie
The mitochondrial F-ATPase can be activated either by the classical cofactor Mg2+ or, with lower ... more The mitochondrial F-ATPase can be activated either by the classical cofactor Mg2+ or, with lower efficiency, by Ca2+. The latter may play a role when calcium concentration rises in mitochondria, a condition associated with cascade events leading to cell death. Common and distinctive features of these differently activated mitochondrial ATPases were pointed out in swine heart mitochondria. When Ca2+ replaces the natural cofactor Mg2+, the enzyme responsiveness to the transmembrane electrochemical gradient and to the classical F-ATPase inhibitors DCCD and oligomycin as well as the oligomycin sensitivity loss by thiol oxidation, are maintained. Consistently, the two mitochondrial ATPases apparently share the F1FO complex basic structure and mechanism. Peculiar cation-dependent properties, which may affect the F1 catalytic mechanism and/or the FO proton binding site features, may be linked to a different physiological role of the mitochondrial Ca-activated F-ATPase with respect to the Mg-activated F-ATPase.
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Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2011
Tributyltin (TBT), widely employed in the past in antifouling paints, is one of the most toxic or... more Tributyltin (TBT), widely employed in the past in antifouling paints, is one of the most toxic organic pollutants. Although recently banned, it still threatens coastal water ecosystems and accumulates in filter-feeding molluscs. TBT is known to act as a membrane-active toxicant; however data on mussels are scanty and exposure effects on mitochondrial ATPase activities remain hitherto unexplored. TBT effects on
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Most of the biological effects displayed by organotin contaminants, among which trisubsituted spe... more Most of the biological effects displayed by organotin contaminants, among which trisubsituted species are especially toxic, have increasingly been found to exhibit astonishing analogies in different taxa. While similarities can be perceived from prokaryotes to mammals, different modes and extent of biochemical and biological effects were described in different cells, tissues and species. A broad susceptibility range to organotins emerges from literature. Aquatic biota are mainly affected by organotins as environmental water and sediments act as storage site. Endocrine and lipid homeostasis perturbations span from Mollusks, where first gender changes (imposex) referable to environmental organotin contamination was pointed out, to Mammals, where organotins play the role of environmental obesogens. Organotin immunotoxicity, elicited in various invertebrate Phyla, also affects humans. Inhibition of key membrane-bound enzyme complexes such as Na.K-ATPase and F0F1 complexes, thus affectin...
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Environmental Toxicology and Chemistry, Jan 30, 2012
The use of tributyltin (TBT) as a biocide in antifouling paints leads to a ruinous input of this ... more The use of tributyltin (TBT) as a biocide in antifouling paints leads to a ruinous input of this contaminant in the aquatic environment. Human exposure to TBT mainly occurs through ingestion of contaminated seafood such as filter-feeding mollusks. Tributyltin is known to act as a membrane-active toxicant on several targets, but especially on the mitochondria, and by several mechanisms. The effects of tributyltin on fatty acid composition, on Mg-adenosine triphosphatase (ATPase) activities, and on the membrane physical state ...
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International Journal of Molecular Sciences
Hydrogen sulfide (H2S) is now considered not only for its toxicity, but also as an endogenously p... more Hydrogen sulfide (H2S) is now considered not only for its toxicity, but also as an endogenously produced gas transmitter with multiple physiological roles, also in maintaining and regulating stem cell physiology. In the present work, we evaluated the effect of a common H2S donor, NaHS, on porcine vascular wall–mesenchymal stem cells (pVW–MSCs). pVW–MSCs were treated for 24 h with increasing doses of NaHS, and the cell viability, cell cycle, and reactive oxygen species (ROS) production were evaluated. Moreover, the long-term effects of NaHS administration on the noteworthy characteristics of pVW–MSCs were analyzed. The MTT test revealed no alteration in cell viability, however, the cell cycle analysis demonstrated that the highest NaHS dose tested (300 μM) determined a block in S phase, which did not depend on the ROS production. Moreover, NaHS (10 μM), continuously administered in culture for 21 days, was able to significantly reduce NG2, Nestin and PDGFR-β expression. The pro-angio...
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Toxicology in Vitro, Mar 9, 2011
The toxicity of organotins and especially tri-n-butyltin (TBT) on mitochondria is well known. How... more The toxicity of organotins and especially tri-n-butyltin (TBT) on mitochondria is well known. However as far as we are aware, effects on mitochondrial respiration are unexplored in mollusks. In this work mitochondria isolated from the digestive gland of Mytilus galloprovincialis and susceptive to the classical respiratory chain inhibitors, were assayed in the presence of micromolar TBT concentrations to investigate mitochondrial respiratory activities. Intact and freeze–thawed mitochondria were used. TBT significantly inhibited ...
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Toxicology in Vitro, Feb 28, 2011
Tri-n-butyltin (TBT) has long been considered as the most toxic among organotins, especially to m... more Tri-n-butyltin (TBT) has long been considered as the most toxic among organotins, especially to membrane systems. The partially dealkylated derivative di-n-butyltin (DBT) has up to now received poor attention and, whenever considered, shown to be less toxic than TBT except on the immune system. The present kinetic approach evidences that both TBT and DBT in vitro inhibit the Mg-ATPase in mussel digestive gland mitochondria by a different mechanism. DBT even displays a higher efficiency than TBT (IC50= 0.32 μM for TBT vs. ...
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