Papers by Antonio Toninello
Inorganica Chimica Acta, 1983
Abstract Inorganic phosphate and Ca 2+ in the incubation medium induce a parallel efflux of endog... more Abstract Inorganic phosphate and Ca 2+ in the incubation medium induce a parallel efflux of endogenous Mg 2+ and adenine nucleotides from rat liver mithochondria [1]. At first no release of accumulated Ca 2+ occurs during Mg 2+ efflux; however as soon as 50% of endogenous Mg 2+ has been lost, Ca 2+ begins to escape as well. It was also shown that addition of Mg 2+ to deenergized mitochondria restores the original membrane potential and confers to mitochondria the full capacity to reaccumulate the Ca 2+ lost [2]. Here, we report that the membrane potential of liver mitochondria incubated in the presence of Ca 2+ and phosphate is preserved by Mn 2+ and restored by the same cation plus ATP or ADP when collapsed. In the typical experiment reported in Fig. 1 Δψ of liver mitochondria, incubated in the presence of Ca 2+ and Pi was fully preserved by 50 μM Mn 2+ . Furthermore, when Mn 2+ was added to mitochondria deenergized by the action of external Ca 2+ and phosphate, Mn 2+ restored the original Δψ provided that ADP was also added. Concordantly, as shown in Fig. 2, Mn 2+ prevented the parallel efflux of endogenous Mg 2+ and adenine nucleotides induced by the flux of Ca 2+ and phosphate. This action of Mn 2+ is very similar to that of Mg 2+ with three major differences: (1) Mn 2+ is active at much lower concentrations; Mg 2+ exhibits the same action [2] of 50 μ M Mn 2+ when added in concentrations above 1 m M. (2) Unlike Mg 2+ , Mn 2+ restores collapsed Δψ only when added together with ATP or ADP. (3) Mg 2+ are unable to restore collapsed Δψ if Mn 2+ are previously added. These results showed that Mg 2+ can be replaced by Mn 2+ in some of their roles in mitochondria and provide preliminary evidence that Mg 2+ and Mn 2+ compete for the same binding sites located on the inner mitochondrial membrane. This assumption explains the inability of Mg 2+ to act as once Mn 2+ has been added to the mitochondrial suspension.
Biochemical and Biophysical Research Communications, Feb 1, 1995
Cannabinoid type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) induces neuroprot... more Cannabinoid type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) induces neuroprotection against brain ischemia, and the mechanism, however, is still elusive. In this study, we used bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation (OGD) in primary cultured neurons to mimic brain ischemic injury, and hypothesized that cannabinoid CB1 receptor agonist ACEA protects ischemic neurons via inhibiting the opening of mitochondrial permeability transition pore (MPTP). In vivo, we found that BCCAO treatment reduced the neurological functions, increased the number of apoptotic neuronal cells and deteriorated the mitochondrial morphology in the ischemic brain tissue. And in vitro, we observed that OGD injury reduced cell viability, mitochondrial function and anti-oxidant SOD2 expression, increased lactate dehydrogenase (LDH), mitochondrial cytochrome C (Cyto C) and apoptosis-inducing factor (AIF) releases, elevated the cell apoptosis and mitochondrial superoxide level. And the CB1 receptor agonist ACEA significantly abolished the BCCAO and OGD-induced neuronal injury above. However, the MPTP opener atractyloside (Atr) markedly reversed the ACEA-induced neuroprotective effects, inhibited the mitochondrial Cyto C and AIF releases and relieved the mitochondrial swelling, but the MPTP inhibitor cyclosporin A (CsA) did not cause significant effects on the ACEA-induced neuroprotection above. These findings indicated that inhibition of MPTP opening may be involved in the cannabinoid CB1 receptor agonist ACEA-induced neuroprotection.
Cardiac muscle is a typical aerobic tissue; its metabolism is closely dependent on oxygen, so tha... more Cardiac muscle is a typical aerobic tissue; its metabolism is closely dependent on oxygen, so that oxygen restriction leads to more or less profound functional and structural damages. Myocardial cells are extremely rich in mitochondria, which occupy ~ 40 per cent of the cellular volume, in myoglobin, and in carnitine (1.3 μmoles/g wet wt of tissue). More than 95 per cent of the ATP utilized in contraction is produced by oxidative phosphorylation.
Biochemical Pharmacology, Sep 1, 1979
PubMed, Oct 1, 1984
The most important biochemical derangements in ischemic myocardium are the decrease of energy ric... more The most important biochemical derangements in ischemic myocardium are the decrease of energy rich phosphates (ATP and phosphocreatine) and intracellular acidosis, both of which contribute to a rapid loss of the contractile function. How and to which extent the alterations of carbohydrate and lipid metabolism are involved in these derangements is briefly discussed. In conditions of oxygen restriction the synchronism between the cytosolic and mitochondrial phase of carbohydrate metabolism is disrupted and beta-oxidation of long chain fatty acids is prevented. Consequently less ATP and more lactate is produced and fatty acids accumulate together with their activation products, acyl CoA in particular. In ischemia free carnitine is also decreased and the carnitine dependent functions (acyl transfer across mitochondrial membrane and pyruvate and alpha ketoglutarate dehydrogenase stimulation) impaired. The meaning of the altered carnitine dependent functions is considered together with the possible (demonstrated and supposed) metabolic effects of carnitine administration in cardiac ischemia.
Biochemical Pharmacology, Aug 1, 1986
The main feature of the esteric group is its ability to accept hydrogen bonds as its oxygen is a ... more The main feature of the esteric group is its ability to accept hydrogen bonds as its oxygen is a typical electron donor group. Probably any other functional group having the same hydrogen bonding accepting capability would display similar behaviour and in effect this could be the case of the 3CN group previously discussed. It is worth mentioning the hypothesis, supported by crystallographic. quantum-mechanic and structure-activity studies. that BDZs also interact with their receptor mainly via hydrogen bonds and in an essentially planar molecular conformation [ 16, 171.
Biochimica Et Biophysica Acta - Biomembranes, May 1, 1985
Spermine, a polyamine present in the mammalian cells at rather high concentration, has, among oth... more Spermine, a polyamine present in the mammalian cells at rather high concentration, has, among other actions, a remarkable stabilizing effect on mitochondria, functions which have generally been attributed to the capability of this and other polyamines to bind to membrane anionic sites. In the present paper evidence is provided that at physiological concentrations spermine may also be transported into rat liver mitochondrial matrix space, provided that mitochondria are energized and inorganic phosphate is simultaneously transported. The close dependence of spermine transport is also demonstrated by the concurrent efflux of spermine and inorganic phosphate when mitochondria preloaded with the two ionic species are deenergized either with uncouplers or respiratory chain inhibitors. Furthermore, Mersalyl, the known inhibitor of phosphate transport, prevents both spermine uptake and release. Mg 2+ inhibits the transport of spermine conceivably by competing for the some binding sites on the mitochondrial membrane. The physiological significance of these results is discussed.
Cell Death and Disease, Oct 22, 2015
Journal of Medicinal Chemistry, Mar 19, 2013
Herein we report the synthesis of new bifunctional sigma-1 (σ 1)-selective ligands with antioxida... more Herein we report the synthesis of new bifunctional sigma-1 (σ 1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands and displayed high affinity and selectivity for σ 1 receptors (K i σ 1 = 1.8 and 5.5 nM; K i σ 2 /σ 1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress. 10 Many investigations have documented the involvement of σ receptors in some important pathways implicated in different neurodegenerative illnesses such as Alzheimer's, 11 Lou Gehrig's 12 and Parkinson's 13,14 diseases. It has been observed that some general pathways, such as an increase in the intracellular calcium levels, mitochondrial dysfunction, reactive species production, metal dyshomeostasis and protein misfolding, participate in the pathogenic cascades of these diseases. 15 In particular, mitochondrial damage increases the production of reactive oxygen species (ROS) and the susceptibility to cell death, playing a key role in these diseases. 16 Recently, the σ 1 protein has been characterized as a chaperone localized to the endoplasmic reticulum (ER) at the mitochondria-associated Page 2 of 37 ACS Paragon Plus Environment Journal of Medicinal Chemistry 1 is based on its antioxidant properties and have found that this compound has neuroprotective effects. 31-33 Thus, our design strategy is based to the development of σ 1 agonists with improved antioxidant properties. To achieve this goal, we combined the structure of 1 with an appropriate aminic moiety
Palmitoyl CoA and palmitoyl carnitine added to rat heart mitochondria in amounts above 20 and 50 ... more Palmitoyl CoA and palmitoyl carnitine added to rat heart mitochondria in amounts above 20 and 50 nmoles/mg protein, respectively, induced a fall in transmembrane potential and loss of endogenous Mg2+. The dissipation of membrane potential by low concentrations of palmitoyl CoA in the presence of Ca2+, but not that of high concentrations of palmitoyl CoA alone, was prevented by either ruthenium red, Cyclosporin A or Mg2+, but reversed only by Mg2+. The fall of membrane potential induced by palmitoyl carnitine was not prevented by any of these factors. It is suggested that the action of both palmitoyl CoA and palmitoyl carnitine at high concentrations is due to a non specific disruption of membrane architecture, while that of low concentrations of palmitoyl CoA in the presence of Ca2+ is associated specifically with energy dissipation due to Ca2+ cycling.
Biochemical and Biophysical Research Communications, Aug 1, 1993
The Journal of Experimental Biology, Nov 15, 2000
Zosterisessor ophiocephalus (Pallas) normally exhibit bioenergetic variables (membrane potential ... more Zosterisessor ophiocephalus (Pallas) normally exhibit bioenergetic variables (membrane potential 165±7 mV; respiratory control ratio 6.6±0.4; ADP/O ratio 1.85±0.8; means ± S.E.M., N=6) and activities of physiological transport systems (phosphate/proton symporter, adenine nucleotide antiporter, Ca 2+ electrophoretic uniporter) comparable with those of rat liver mitochondria. When incubated in the presence of Ca 2+ and an inducer agent such as phosphate, these mitochondria undergo a complete collapse of membrane potential accompanied by a large-amplitude swelling of the matrix, influx of sucrose from the incubation medium, release of endogenous Mg 2+ and K + (approximately 90 % of the total) and of preaccumulated Ca 2+ and oxidation of endogenous pyridine nucleotides. All these phenomena, which are completely eliminated by cyclosporin A and inhibited with different efficacies by Mg 2+ and spermine, demonstrate that the induction of the permeability transition in this type of mitochondria has characteristics similar to those described in rat liver mitochondria. In contrast, the requirement for very high Ca 2+ concentrations (greater than 100 µmol l -1 ) for the induction of the permeability transition represents a very important difference that distinguishes this phenomenon in fish and mammalian mitochondria.
Analele Stiintifice ale Universitatii "Alexandru Ioan Cuza" din Iasi Sec. II a. Genetica si Biologie Moleculara, Aug 15, 2004
Current Medicinal Chemistry, Sep 1, 2004
Current Pharmaceutical Design, Jan 31, 2014
Mitochondria are the cell powerhouses but also contain the mechanisms leading to cell death. Many... more Mitochondria are the cell powerhouses but also contain the mechanisms leading to cell death. Many signals converge on mitochondria to cause the permeabilization of mitochondrial membranes by the mitochondrial permeability transition (MPT) induction and the opening of transition pores (PTPs). These events cause loss of ionic homeostasis, matrix swelling, outer membrane rupture leading to pro-apoptotic factors release, and impairment of bioenergetics functions. The molecular mechanism underlying MPT induction is not completely elucidated however, a growing body of evidence supports the concept that pharmacological induction of PTPs in mitochondria of neoplastic cells is an effective and promising strategy for therapeutic approaches against cancer. The first part of this article presented as a review also evidences the main constituents of PTP and several compounds targeting them for inducing the phenomenon. The second part of the article regards the recent experimental development in the field, in particular, the effects of peniocerol (PEN), a sterol isolated from the root of Myrtillocactus geometrizans, at cellular and mitochondrial level. PEN exhibits a cytotoxic activity on some human tumor cell lines, whose mechanism is attributable to the oxidation of critical thiols located on adenine nucleotide translocase, the protein mainly involved in PTP. This event in the presence of Ca 2+ induces the MPT with the release of the pro-apoptotic factors cytochrome c and apoptosis inducing factor. These observations evidence that PEN may trigger both the caspase-dependent and caspaseindependent apoptotic pathways. This characteristic renders PEN a very interesting compound that could be developed to obtain more effective antiproliferative agents targeting mitochondria for anticancer therapy.
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Papers by Antonio Toninello