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Managò, Antonella (2016) Mitochondrial potassium homeostasis and its relevance in pathophysiological contexts. [Ph.D. thesis]

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Abstract (italian or english)

During my Ph.D., my research focused on the involvement and the role of mitochondrial potassium homeostasis in the context of pathophysiological processes. I have been working on three related projects, for which the common aspect is the study of the mitochondrial potassium homeostasis and its modulation by pharmacological tools. My thesis contains a general introduction, in order to give a general up-to-date overview covering all the topics treated during my Ph.D., followed by a collection of the papers where I gave my contribution.

Concerning the first project, my studies provided new insights into the mechanism of action of an emerging pro-apoptotic, oncologically relevant molecule, namely salinomycin. This molecule was considered a valinomycin-like K+ ionophore. Its recent identification as a selective inducer of apoptosis in cancer stem cells (CSCs) and different types of non-stem cancer cells, together with the ability to spare healthy cells, led to an increased interest in unravelling its mechanism of action, poorly understood so far. Moreover, since salinomycin has been suggested to act as a K+ ionophore, it is expected to impact mitochondrial function; however detailed information on its mitochondrial effects were not available from the literature. Therefore, I explored its early effects on mitochondrial bioenergetics. In order to do this, I compared its activity with that of valinomycin (K+ ionophore) or of nigericin (K+/H+ exchanger), for which the action was already well defined by others in the past.
By using different approaches, ranging from classical bioenergetic studies on isolated mitochondria to more innovative measurement of bioenergetic parameters on intact cells, and of course by exploiting different cellular biology techniques, it has been concluded that salinomycin mediates K+/H+ exchange across the inner mitochondrial membrane, similarly to nigericin. It has been observed that salinomycin was also able to induce cell death of cells lacking some crucial actors of the apoptotic pathway (Bax/Bak-less double- knockout MEF cells). These results were compatible with the idea of direct modulation of mitochondrial function. At this point, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects has been investigated. The results indicated that salinomycin, when used above μM concentrations, exerts direct, mitochondrial effects, thus compromising cell survival, even in non-tumoral cells. These results were published in Managò et al., Cell Death and Disease, 2015.

Having acquired the “know-how” to assess mitochondrial bioenergetic functions, I also actively contributed to a project carried out in collaboration with Prof. Erich Gulbins from University of Essen (Germany), where I also spent five months of my Ph.D. A strict collaboration between the lab where I did my Ph.D. and the lab of Prof. Gulbins led to the discovery of a mitochondrial voltage-gated potassium channel, mtKv1.3 and to the clarification of its important role during apoptosis. Mechanistically, it has been demonstrated that the pro-apoptotic protein Bax directly interacts with and inhibits mtKv1.3, via a toxin-like mechanism. The direct inhibition of mtKv1.3 leads to hyperpolarization, mitochondrial ROS production, opening of the permeability transition pore (PTP), release of cytochrome c and finally to apoptosis. In accordance to this model, direct pharmacological inhibition of mtKv1.3 by using the membrane-permeant Kv1.3 inhibitors Psora-4, PAP-1 and clofazimine leads to cell death in different types of cancer, as demonstrated by our group.

The starting point of my second project was the fact that pyocyanin, a membrane-permeant toxin released by the Gram-negative bacterium Pseudomonas aeruginosa shows structural similarity to clofazimine, a membrane-permeant mtKv1.3 inhibitors. P. aeruginosa causes lung infections in immunocompromised patients and it is known that pyocyanin induces death of neutrophils, which plays an important role in the host’s early acute defence against pulmonary P. aeruginosa infections. However the exact mechanism of action of pyocyanin is still unknown therefore we determined whether its effect is related to Kv1.3 expression, given the crucial role of mtKv1.3 in apoptosis and the structural similarity of pyocyanin to mtKv1.3 inhibitors. First of all, it was observed by patch clamp experiments that pyocyanin is able to inhibit Kv1.3 current. At low concentration (up to 10µM), pyocyanin induced cell death preferentially in cells expressing Kv1.3. However, in the literature pyocyanin was mostly used at higher concentrations (50-100 µM), since in the sputum of patients with P. aeruginosa infections it might reach such a high concentration. Moreover, data from the literature suggested that pyocyanin might have a mitochondrial action and is able to produce high amounts of reactive oxygen species (ROS). Therefore, it has been investigated how pyocyanin impacts on mitochondrial function on a short time scale when used at high concentration (at 50µM). Again, intact cells or isolated mitochondria were used to assay the effect of this compound. It has been shown that pyocyanin determines an instantaneous production of superoxide anion at mitochondrial sites and a rapid but incomplete dissipation of the mitochondrial membrane potential. Further, it has been observed that pyocyanin can replace the function of complex III, while it does not directly alter the function of complex I. Moreover, it has been shown that ROS production induced by pyocyanin activates the acid sphyngomyelinase, shown to be present in mitochondria. This event in turn leads to the formation of ceramide, induction of apoptosis and release of cytochrome c. Genetic deficiency of acid sphyngomyelinase or scavenging of ROS induced by pyocyanin prevented cell death in neutrophils, meaning that pyocyanin, at high concentrations, induces cell death via mitochondrial reactive oxygen species and mitochondrial acid sphyngomyelinase, independently of the expression of the voltage gated potassium channel Kv1.3. These results were published in Managò et al., Antioxidant and redox signaling, 2015.

During the last period of my Ph.D, I also studied the effect of newly synthesized Psoralen derivatives and clofazimine for the treatment of cancer. Concerning the first group, they are specific inhibitors of the voltage gated potassium channel Kv1.3; the second one is a molecule already in use in clinic to treat pathologies like leprosy, which also inhibits Kv1.3 current. Due to their lipophilic structure, they are all membrane-permeant, therefore able to reach intracellular membranes, like inner mitochondrial membrane where the voltage gated potassium channel Kv1.3 is also expressed and active. As mentioned above, the specific inhibition of mtKv1.3 triggers cell death. It has previously been demonstrated that Psora-4, PAP-1 (Psoralen derivatives) and clofazimine are able to specifically induce apoptosis in cancer cells in vitro on many cancer cell lines, ex vivo on B-CLL (chronic lymphocytic leukaemia) cells obtained from patients and in vivo on melanoma tumour model. Following these promising results, in collaboration with Professor Cristina Paradisi (Department of Chemical Sciences, University of Padova), PAP-1 and clofazimine derivatives have been synthesized in order to make these molecules more soluble and mitochondriotropic (i.e.: increased tendency to target mtKv1.3).
I tested the ability of these new compounds to induce cell death in cancer cells first in vitro. Since the results obtained on different cell lines in vitro were promising and death was strictly dependent on Kv1.3 expression, it has been decided to test these compounds also in vivo on a melanoma model and on a pancreatic cancer model. During my 2-month stay at the end of the first year of my Ph.D. at the Institute for Experimental Cancer Research, University of Kiel (Germany), I performed in vivo experiments, using PAP-1 derivatives and clofazimine on SCID mouse injected with Colo357, a human pancreas tumour Kv1.3 expressing cell line, obtaining a significant reduction of the mass of the tumour (Zaccagnino, Managò et al., under submission to Oncotarget). Moreover, PAP-1 derivatives have been tested on a melanoma model in vivo, obtaining relevant results (Leanza, Romio, Becker, Azzolini, Trentin, Managò et al., manuscript in preparation, not included in the present thesis). The treatment exerted an effect on cancer, without significant side effects on healthy tissues.
Some of the most promising clofazimine-derivatives have been selected to be tested on cells deriving from acute myeloid leukaemia (AML) patient. I carried out these experiments during my stay in Germany at the Department of Molecular Biology University of Duisburg-Essen. Blood samples came directly from the haematology ward of the university-hospital in Essen. So far, we obtained preliminary results which are however controversial, since different patients were diagnosed at different stage of the disease (i.e. have different levels of pathological cells) and AML itself is a heterogeneous disease at the molecular and cytogenetic level. Therefore this work has not been included in the thesis.

Furthermore, I took part in a project of the laboratory of Prof. Holger Kalthoff (University of Kiel, Germany), concerning the study of the mechanism of action of a seaweed extract, for which I performed the experiments of bioenergetics (Geisen , Zenthoefer , Peipp , Kerber , Plenge , Managò et al., Marine drugs, 2015).
Beside the laboratory-based projects, I also contributed to the preparation of two reviews, one concerning intracellular ion channels and cancer (Leanza, Biasutto, Managò et al., Frontiers on Physiology, 2013) and the other regarding in vivo pharmacological targeting of ion channels as possible therapeutic tool against cancer (Leanza, Managò et al., BBA Mol. Cell Research, 2015).

Abstract (a different language)

Durante il mio dottorato, la mia ricerca si è concentrata sul coinvolgimento e il ruolo dell'omeostasi mitocondriale di potassio (K+) in processi fisiopatologici. Ho lavorato su tre progetti correlati, per cui l'aspetto comune è lo studio dell’omeostasi del potassio mitocondriale e la sua modulazione tramite strumenti farmacologici. La mia tesi contiene un'introduzione generale, al fine di dare una descrizione generale aggiornata di tutti gli argomenti trattati durante il mio dottorato di ricerca, seguiti da una raccolta di pubblicazioni scientifiche in cui ho dato il mio contributo.

Per quanto riguarda il primo progetto, i miei studi hanno fornito nuove informazioni sul meccanismo d'azione di una molecola pro-apoptotica emergente, rilevante dal punto di vista oncologico, nota come salinomicina. Questa molecola è stata considerata uno ionoforo di K+ simile alla valinomicina. La sua recente identificazione come induttore selettivo di apoptosi in cellule staminali tumorali (CSCs) e diversi tipi di cellule tumorali non-staminali, insieme alla sua capacità di risparmiare le cellule sane, ha portato a un interesse crescente verso la comprensione del suo meccanismo d'azione, poco noto finora. Inoltre, poiché è stato suggerito che la salinomicina agisca come uno ionoforo di K+, ci si aspetta un suo effetto sulla funzione mitocondriale. Tuttavia non erano disponibili in letteratura informazioni dettagliate sugli effetti mitocondriali di questa molecola. Pertanto, ho esplorato i suoi effetti istantanei sulla bioenergetica mitocondriale. Per fare questo, ho confrontato la sua attività con quella della valinomicina (ionoforo di K+) e della nigericina (scambiatore K+/H+), l'azione delle quali era già stata ben definita da altri in passato.
Utilizzando diversi approcci, che vanno dagli studi bioenergetici classici su mitocondri isolati alla misurazione di parametri bioenergetici con strumenti più innovativi su cellule intatte, e, naturalmente, sfruttando diverse tecniche di biologia cellulare, si è concluso che la salinomicina media lo scambio K+/H+ attraverso la membrana mitocondriale interna , analogamente alla nigericina. Inoltre, è stato visto che la salinomicina è stata in grado di indurre la morte cellulare delle cellule prive di alcuni attori cruciali del processo apoptotico (doppio knock-out di Bax/Bak in cellule MEF). Questi risultati sono compatibili con l'idea di una modulazione diretta della funzione mitocondriale da parte della salinomicina. A questo punto, è stata studiata la specificità della sua azione su cellule B patologiche isolate da pazienti con leucemia linfatica cronica (CLL) versus cellule B di soggetti sani. I risultati hanno indicato che la salinomicina, quando usata sopra concentrazioni mM, esercita effetti mitocondriali diretti, compromettendo così la sopravvivenza delle cellule, anche di quelle non tumorali. Questi risultati sono stati pubblicati in Managò et al., Cell Death and Disease, 2015.

Avendo acquisito il "know-how" per valutare le funzioni bioenergetiche mitocondriali, ho anche contribuito attivamente a un progetto realizzato in collaborazione con il Prof. Erich Gulbins dell'Università di Essen (Germania), dove ho anche trascorso cinque mesi del mio dottorato di ricerca. Una stretta collaborazione tra il laboratorio dove ho fatto il mio dottorato di ricerca e il laboratorio del Prof. Gulbins ha portato alla scoperta di un canale del potassio voltaggio-dipendente mitocondriale, mtKv1.3 e al chiarimento del suo importante ruolo durante l'apoptosi. Meccanicisticamente, è stato dimostrato che la proteina pro-apoptotica Bax interagisce direttamente con mtKv1.3 e lo inibisce, tramite un meccanismo simile a quello di alcune tossine. L'inibizione diretta di mtKv1.3 porta ad iperpolarizzazione, produzione di ROS a livello mitocondriale, apertura del poro di transizione di permeabilità (PTP), rilascio di citocromo c ed infine all'apoptosi. Secondo questo modello, l'inibizione farmacologica diretta di mtKv1.3 utilizzando inibitori di Kv1.3 permeanti la membrana come Psora-4, PAP-1 e clofazimina, porta alla morte cellulare in diversi tipi di cancro, come dimostrato dal nostro gruppo.
Il punto di partenza del mio secondo progetto è stato l’evidenza che la piocianina, una tossina permeante la membrana rilasciata dal batterio Gram-negativo Pseudomonas aeruginosa mostra somiglianza strutturale alla clofazimina, un inibitore di Kv1.3 permeante la membrana. P. aeruginosa provoca infezioni polmonari nei pazienti immunocompromessi ed è noto che la piocianina induce morte cellulare nei neutrofili, che svolgono un ruolo importante nella difesa precoce acuta dell'ospite contro infezioni polmonari da P. aeruginosa. Tuttavia l'esatto meccanismo d'azione della piocianina è ancora sconosciuta quindi abbiamo voluto studiare se il suo effetto è legato all'espressione di Kv1.3, dato il ruolo cruciale di mtKv1.3 nell’apoptosi e l'affinità strutturale della piocianina agli inibitori di Kv1.3. Prima di tutto, è stato osservato dagli esperimenti di patch-clamp che la piocianina è in grado di inibire la corrente di Kv1.3. A basse concentrazioni (fino a 10 µM), la piocianina induce morte cellulare preferenzialmente in cellule esprimenti Kv1.3. Tuttavia, in letteratura la piocianina è stata utilizzata principalmente a concentrazioni più elevate (50-100 µM), poiché nell'espettorato di pazienti con infezioni da P. aeruginosa potrebbe raggiungere tale concentrazioni. Inoltre, diversi dati in letteratura hanno suggerito che la piocianina potrebbe avere un'azione mitocondriale ed è in grado di produrre elevate quantità di specie reattive dell'ossigeno (ROS). Pertanto, è stato esaminato l'impatto della piocianina sulla funzione mitocondriale con cinetiche brevi, quando usata ad alta concentrazione (50 µM). Ancora una volta, cellule intatte o mitocondri isolati sono stati usati per saggiare l'effetto di questo composto. E 'stato osservato che la piocianina determina una produzione istantanea di anione superossido a livello di siti mitocondriali e una dissipazione rapida ma incompleta del potenziale di membrana mitocondriale. Inoltre, è stato visto che la piocianina può sostituire la funzione del complesso III, mentre non altera direttamente la funzione del complesso I. Infine, è stato dimostrato che la produzione di ROS indotta dalla piocianina attiva la sfingomielinasi acida, presente anche in mitocondri. Questo evento a sua volta porta alla formazione di ceramide, induzione di apoptosi e rilascio del citocromo c. La mancanza di espressione della sfingomielinasi acida o lo scavenging di ROS indotta dalla piocianina impedisce la morte cellulare in neutrofili, che indicando che la piocianina, ad alte concentrazioni, induce la morte cellulare attraverso specie reattive dell'ossigeno mitocondriali e sfingomielinasi acida mitocondriale, indipendentemente dall'espressione del canale del potassio voltaggio dipendente Kv1.3. Questi risultati sono stati pubblicati in Managò et al., Antioxidant and redox signaling, 2015.

Durante l'ultimo periodo del mio dottorato di ricerca, ho anche studiato l'effetto di alcuni derivati di psoraleni di nuova sintesi e della clofazimina per il trattamento del cancro. Per quanto riguarda il primo gruppo, essi sono inibitori specifici del canale del potassio voltaggio dipendente Kv1.3; la seconda è una molecola già in uso in clinica per il trattamento di patologie come la lebbra, che agisce anche come inibitore della corrente di Kv1.3. Grazie alla loro struttura lipofila, sono tutti permeanti la membrana, quindi in grado di raggiungere le membrane intracellulari, come la membrana mitocondriale interna dove il canale del potassio voltaggio dipendente Kv1.3 è espresso e attivo. Come accennato in precedenza, l'inibizione specifica di mtKv1.3 innesca la morte cellulare. È stato dimostrato che Psora-4, PAP-1 e clofazimina sono in grado di indurre specificamente apoptosi nelle cellule tumorali in vitro su molte linee cellulari tumorali, ex vivo su cellule B ottenute da pazienti con leucemia linfatica cronica e in vivo su modello di melanoma. A seguito di questi risultati promettenti, in collaborazione con la Prof. Cristina Paradisi (Dipartimento di Scienze Chimiche, Università di Padova), sono stati sintetizzati derivati del PAP-1 e della clofazimina in modo da rendere queste molecole più solubili e mitocondriotropiche (i.e.: indirizzate al mitocondrio).
Ho testato prima la capacità di questi nuovi composti di indurre morte cellulare nelle cellule tumorali in vitro. Poiché i risultati ottenuti su diverse linee cellulari sono stati promettenti e l’induzione di morte cellulare era strettamente dipendente dalla espressione Kv1.3, si è deciso di testare questi composti anche in vivo in un modello di melanoma e di tumore pancreatico. Durante il mio soggiorno di due mesi al termine del primo anno di mio dottorato presso l'Istituto per la ricerca sperimentale sul cancro, Università di Kiel (Germania), ho eseguito esperimenti in vivo, usando derivati del PAP-1 e clofazimina su topi SCID iniettati con Colo357, una linea di cellule tumorali umane di pancreas esprimenti Kv1.3, ottenendo una riduzione significativa della massa del tumore (Zaccagnino, Managò et al., under submission alla rivista Oncotarget). Inoltre, i derivati del PAP-1 sono stati testati su un modello in vivo di melanoma, dando risultati rilevanti (Leanza, Romio, Becker, Azzolini, Trentin, Managò et al., manoscritto in preparazione, non incluso nella presente tesi). Il trattamento ha esercitato un effetto sul tumore, senza rilevanti effetti collaterali sui tessuti sani.
Alcuni dei più promettenti derivati della clofazimina sono stati selezionati per essere testati su cellule derivanti da pazienti con leucemia mieloide acuta (AML). Ho eseguito questi esperimenti durante il mio soggiorno in Germania presso il Dipartimento di Biologia Molecolare dell'Università di Duisburg-Essen. I campioni di sangue provenivano direttamente dal reparto di ematologia della clinica universitaria di Essen. Finora, abbiamo ottenuto risultati preliminari che sono però controversi, poiché i pazienti sono stati diagnosticati a diversi stadi della malattia (cioè hanno livelli differenti di cellule patologiche nel sangue) e poiché la leucemia mieloide acuta è di per sé una malattia eterogenea a livello molecolare e citogenetico. Questi studi non sono stati inclusi nella tesi.

Inoltre, ho partecipato a un progetto del laboratorio del Prof. Holger Kalthoff (Università di Kiel, Germania), riguardante lo studio del meccanismo d'azione di un estratto di alghe marine, per il quale ho eseguito gli esperimenti di bioenergetica (Geisen, Zenthoefer, Peipp, Kerber, Plenge, Managò et al., Marine drugs, 2015).
Oltre ai progetti basati sull’attività in laboratorio, ho anche contribuito alla preparazione di due review, una in materia di canali ionici intracellulare in relazione al cancro (Leanza, Biasutto, Managò et al., Frontiers on Physiology, 2013) e l'altra riguardante l’utilizzo in vivo di canali ionici come bersaglio farmacologico come possibile strumento terapeutico nella cura del cancro (Leanza, Managò et al., BBA Mol Cell. Research, 2015).

Statistiche Download
EPrint type:Ph.D. thesis
Tutor:Szabò, Ildikò
Data di deposito della tesi:30 January 2016
Anno di Pubblicazione:01 February 2016
Key Words:mitocondri-potassio-omeostasi/mitochondria-potassium-homeostasis
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9403
Depositato il:18 Oct 2016 17:22
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