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Battaglia, Valentina (2009) Biogenic amines as regulators of mitochondrial functions: Roles of Agmatine. [Tesi di dottorato]

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Abstract (inglese)

Agmatine is a dicationic amine at physiological pH, formed by decarboxylation of arginine catalyzed by arginine decarboxylase. It acts on polyamine metabolism by inhibiting nitric oxyde synthase and activating spermidine/spermine acetyltransferase as well as the antizyme of ornithine decarboxylase. Agmatine is metabolized by agmatinase to form urea and putrescine, suggesting that it is a polyamine precursor. Agmatine is transported to organs by an energydependent mechanism, whereas increased cellular concentrations promotes apoptosis. Agmatine and its metabolic enzymes arginine decarboxylase and agmatinase have also been recognized in mitochondria, as well as imidazoline I2 receptor. These observations and the results obtained in these years, during my work, evidence a close relationship between agmatine and mitochondria. The aim of this work is to study the action of agmatine as regulator of mitochondrial functions, compared with the effect of polyamines (i.e. spermine), in isolated rat mitochondria from different organs: liver, brain and kidney. The first part of the work focuses on agmatine uptake by mitochondria with characterization of the transport system. A comparison among the agmatine transport mechanism in mitochondria isolated from different organs is reported. In the second part is reported the action of this amine on mitochondrial permeability transition induction, again with the above mentioned comparison but together the effects of spermine. The amine exhibits protective effects against the phenomenon in kidney and brain mitochondria, whereas in liver mitochondria it exhibits double behavior, that is, induction at low concentrations and protection at high concentrations. The possible explanation is the presence of a specific amino oxidase in liver mitochondria. Finally, in the third part, the synthesis of agmatine using an alternative reaction to that of arginine decarboxylase is reported. The presence of an amidinotransferase reaction has been found in rat kidney mitochondria and in a proximal tubule cell line as the results of a first purification step. This observation could correlate the synthesis of agmatine with a regulation mechanism of polyamine concentration in cells. In conclusions the results obtained with this study put in evidence agmatine as a physiological regulator of polyamine content in the cell, rather than a simple polyamine precursor, as proposed by some authors. Moreover, this investigation point out the important physiological role of mitochondria activity as mediators of this process. Indeed, the action of this amine in mitochondrial permeability transition of isolated mitochondria explains its effect on cell proliferation and apoptosis.

Abstract (italiano)

L’agmatina è un’amina è formata dalla decarbossilazione dell’arginina in una reazione catalizzata dall’arginina decarbossilasi ed è caratterizzata dalla presenza di due cariche a pH fisiologico. L’agmatina agisce sul metabolismo delle poliamine inibendo la ossido nitrico sintasi e attivando la spermidina/spermina acetiltransferasi e l’antizima dell’ornitina decarbossilasi. L’agmatina viene metabolizzata dall’agmatinasi formando urea e putrescina, suggerendo che sia un precursore delle poliamine. Viene trasportata agli organi da un meccanismo energia-dipendente e, un aumento della sua concentrazione, promuove l’induzione dell’apoptosi. L’agmatina e gli enzimi del suo metabolismo, arginina decarbossilasi e agmatinasi, così come i recettori imidazolinici I2, ai quali l’amina si lega, sono stati ritrovati nei mitocondri. Queste osservazioni e i risultati ottenuti in questi anni, durante il mio lavoro, evidenziano una stretta relazione tra agmatina e mitocondri. Lo scopo di questa ricerca è studiare l’azione dell’agmatina come regolatore delle funzioni mitocondriali e confrontarne gli effetti con quelli delle poliamine (ad esempio spermina), in mitocondri isolati da organi differenti di ratto: fegato, cervello e rene. La prima parte del lavoro riporta il trasporto dell’agmatina all’interno dei mitocondri e la caratterizzazione del sistema di trasporto. Vengono comparati i meccanismi di trasporto dell’agmatina nei mitocondri isolati dai diversi organi. Nella seconda parte viene riportata l’azione di quest’amina sull’induzione della transizione di permeabilità mitocondriale, di nuovo comparando gli effetti nei diversi organi ma anche con la spermina. L’amina ha un effetto protettivo contro il fenomeno in rene e cervello, mentre nel fegato il suo comportamento è duplice: induce a basse concentrazioni e protegge ad alte. Per spiegare tale differenza, si ipotizza la presenza di una specifica amino ossidasi nei mitocondri di fegato. Infine, nella terza parte, viene studiata la sintesi di agmatina tramite una reazione alternativa all’arginina decarbossilasi. La presenza di una reazione amidinotransferasica è stata riscontrata in mitocondri di rene di ratto e in un linea cellulare di tubulo prossimale. Vengono riportati anche i risultati relativi ad un primo step di purificazione. Queste osservazioni potrebbero correlare la sintesi di agmatina con un meccanismo per la regolazione della concentrazione di poliamine nelle cellule. In conclusione, i risultati ottenuti mettono in evidenza come l’agmatina agisca da regolatore fisiologico del contenuto di poliamine nella cellula piuttosto che comportarsi come un semplice precursore delle poliamine, come viene considerata da alcuni autori. Questa ricerca dimostra, inoltre, come i mitocondri siano importanti mediatori fisiologici di questo processo. Infatti, l’azione di quest’amina sulla transizione di permeabilità mitocondriale spiega i suoi effetti sulla proliferazione cellulare e sull’apoptosi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Toninello, Antonio
Correlatore:Grillo, Maria Angelica
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOCHIMICA E BIOTECNOLOGIE > BIOCHIMICA E BIOFISICA
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):agmatine, mitochondria, polyamines, oxidative stress
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Chimica Biologica
Codice ID:1675
Depositato il:29 Gen 2009
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