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Scalcon, Valeria (2018) CRITICAL ROLE OF THE THIOREDOXIN AND THE GLUTATHIONE
SYSTEMS IN MITOCHONDRIAL PATHOPHYSIOLOGY.
[Ph.D. thesis]

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Abstract (italian or english)

The thioredoxin and the glutathione systems are important thiol redox regulating networks. The mitochondrial thioredoxin system is composed by NADPH, thioredoxin reductase 2 (TrxR2) and thioredoxin 2 (Trx2) that, in turn, can reduce peroxiredoxin 3 (Prx3) which has a hydroperoxide scavenging activity.
Cyclophilin D (CypD) is a small protein of the mitochondrial matrix having a crucial role in the control of the mitochondrial membrane permeability transition. CypD activity and redox state were found to be subjected to thioredoxin system-mediated reduction in both isolated rat heart mitochondria and in human cell lines. Furthermore, CypD interaction with Trx2 and Prx3 was observed with both the co-immunoprecipitation technique and with a molecular docking prediction. Thus, CypD can be redox modulated by the mitochondrial thioredoxin system.
The thiol redox regulating systems, especially TrxR2, are often overexpressed in cancer cells to counteract the increased ROS level due to cancer progression. Therefore, the search for specific TrxR2 inhibitors is a possible new anticancer strategy. Several novel compounds, obtained in the frame of different international collaborations, were studied. In particular, a new Au(III) complex bearing a bidentate N-donor ligand, various cyclometalated 2,6-diphenylpyridine Au(III) complexes and a series of mono and bis N-heterocyclic carbene Au(I) complexes were synthesized and were found to inhibit selectively thioredoxin reductase, disrupting the overall cellular redox homeostasis in human ovarian cancer cell lines.
Afterwards, a class of non-gold based metallodrugs, derived from tamoxifen and called tamoxifen-like metallocifens (TLMs), were studied. Interestingly, TLMs act as pro-drugs. In fact, upon enzymatic oxidation, they can be transformed into new oxidized derivatives endowed with remarkable TrxR2 inhibitory properties. In the lymphoblastoid cell line Jurkat, TLMs-mediated TrxR2 inhibition stimulated Trx2 oxidation, ROS production and intrinsic apoptotic pathway activation.
The effects of TrxR2 genetic depletion was also investigated in different cancer cell lines utilizing the Crispr/Cas9 method. Notably, an inverse correlation between TrxR2 protein level and cellular ROS production was observed, indicating the strong pro-oxidizing condition derived from TrxR2 depletion.
Then, the research was focused on glutaredoxin 2 (Grx2). Grx2 was reported to link the thioredoxin and the glutathione systems, but its specific role in redox signaling events is unclear. Grx2 catalyzes protein de-glutathionylations and can also coordinate an iron-sulfur cluster, forming dimers. Grx2 monomeric and dimeric state was analyzed upon HeLa cells treatment with different oxidizing conditions. Grx2 stayed principally as an inactive dimer, while it dissociated, and its activity was stimulated specifically in the mitochondrial compartment, only upon the combined hindering of both the glutathione and the thioredoxin systems. A large increase of free iron ions in the mitochondrial matrix, induction of lipid peroxidation and decrease of the mitochondrial membrane potential were also observed, indicating that Grx2 monomerization implied the release of the iron-sulfur cluster.
In collaboration with Prof. A. Holmgren’s group at the Karolinska Institutet, the role of Grx2 in mitochondria has been further studied in a murine model knockout for Grx2 in mitochondria (mGrx2 KO). The overall redox state of mitochondria isolated from different organs of WT or mGrx2 KO mice at three months of age was assessed and interestingly it was not affected from Grx2 deletion. However, a significant increase of mitochondrial ROS production was noted in the liver associated to a decrease of the mitochondrial respiratory capacity, to a reduction of the mitochondrial membrane potential and to an increased sensitivity to calcium ions. Altogether, these results suggest that Grx2 deletion in mouse mitochondria affects mainly the mitochondrial functioning in the liver.

Abstract (a different language)

I sistemi della tioredossina e del glutatione sono importanti nella regolazione redox cellulare. Il sistema tioredossinico mitocondriale è composto da NADPH, tioredossina reduttasi 2 (TrxR2) e tioredossina 2 (Trx2) che, a sua volta, può ridurre la perossiredossina 3 (Prx3) la quale detossifica dagli idroperossidi.
La ciclofilina D (CypD) è una proteina di matrice mitocondriale che ha un ruolo cruciale nel controllo della transizione di permeabilità di membrana mitocondriale. È stato visto che l'attività e lo stato redox di CypD sono soggetti a riduzione mediata dal sistema tioredossinico sia in mitocondri isolati che in linee cellulari umane. Inoltre, l'interazione di CypD con Trx2 e Prx3 è stata osservata sia tramite co-immunoprecipitazione che con una molecular docking prediction. Pertanto, CypD viene regolata redox dal sistema tioredossinico mitocondriale.
I sistemi di regolazione redox, e specialmente la TrxR2, sono spesso sovraespressi in cellule tumorali per contrastare l'aumento dei ROS causato dalla progressione tumorale. Pertanto, la ricerca di inibitori specifici della TrxR2 è una possibile strategia antitumorale. Sono stati studiati diversi nuovi composti nell’ambito di varie collaborazioni internazionali. In particolare, un complesso di oro(III) recante un ligando N-bidentato, vari complessi 2,6-difenilpiridinici di oro(III) e una serie di complessi carbenici di oro(I) sono stati sintetizzati e si sono rivelati in grado di inibire selettivamente la tioredossina reduttasi in linee cellulari tumorali ovariche, alterando l’intero equilibrio redox cellulare. In seguito sono stati studiati una classe di composti metallorganici derivati dal tamoxifene denominati tamoxifen-like metallocifens (TLMs). I TLMs sono pro-farmaci. Infatti, tramite ossidazione enzimatica, possono essere trasformati in derivati dotati di notevoli proprietà inibitorie sulla TrxR2. Nella linea cellulare linfoblastoide Jurkat, l'inibizione di TrxR2 indotta dai TLMs porta all'ossidazione di Trx2, alla produzione di ROS e all'attivazione della via apoptotica intrinseca.
Utilizzando il metodo Crispr/Cas9, sono stati anche studiati gli effetti della deplezione genetica di TrxR2 in diverse linee cellulari tumorali. Nei cloni knockdown per TrxR2 è stata osservata una correlazione inversa tra il livello di TrxR2 e la produzione di ROS. Ciò indica la forte condizione pro-ossidante derivante dalla mancanza di TrxR2.
Successivamente la ricerca si è focalizzata sulla glutaredossina 2 (Grx2). La Grx2 collega i sistemi tioredossinico e del glutatione, ma il suo ruolo specifico nella segnalazione redox non è stato ancora chiarito. Grx2 catalizza processi di de-glutationilazione e può anche coordinare un centro ferro-zolfo, formando dimeri inattivi. Per prima cosa lo stato monomerico e dimerico di Grx2 è stato analizzato a seguito del trattamento di cellule HeLa con differenti condizioni ossidanti. Grx2 è stata osservata principalmente come dimero inattivo, mentre può dissociare ed attivarsi specificatamente nel compartimento mitocondriale, solo in seguito all’inibizione di entrambi i sistemi tiolici. Ciò porta ad un aumento del ferro labile nella matrice mitocondriale e conseguenti perossidazione lipidica e diminuzione del potenziale di membrana mitocondriale.
In collaborazione con il gruppo del Prof. A. Holmgren presso il Karolinska Institutet, il ruolo di Grx2 nei mitocondri è stato ulteriormente studiato in un modello murino knockout per Grx2 nel comparto mitocondriale (mGrx2 KO). Lo stato redox di mitocondri deficitari di Grx2 non è stato trovato alterato nei diversi organi isolati da animali mGrx2 KO a tre mesi di età. Tuttavia, a livello epatico, sono stati osservati un aumento significativo della produzione mitocondriale di ROS, una diminuzione della capacità respiratoria e del potenziale di membrana mitocondriale associati ad una maggiore sensibilità degli stessi mitocondri agli ioni calcio. Complessivamente, questi risultati suggeriscono che, nel modello murino, il fegato è il principale organo affetto dalla delezione mitocondriale di Grx2.

EPrint type:Ph.D. thesis
Tutor:Rigobello, Maria Pia
Supervisor:Bindoli, Alberto
Ph.D. course:Ciclo 31 > Corsi 31 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:27 November 2018
Anno di Pubblicazione:30 November 2018
Key Words:Thiol redox regulation, thioredoxin system, glutathione system, anticancer drugs, thioredoxin reductase 2, glutaredoxin 2
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:11393
Depositato il:15 Nov 2019 14:43
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