Abstract Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of kidney cancer, accounting for approximately 80% of renal cell carcinoma cases in adults. The pathogenesis of ccRCC is intricate and multifactorial, with mutations in the von Hippel-Lindau (VHL) gene being a hallmark of the disease. These mutations disrupt normal cellular processes, leading to aberrant activation of hypoxia-inducible factors (HIFs) and subsequent alterations in metabolism, angiogenesis, and cell proliferation. Importantly, mitochondrial alterations are a common feature of RCCs, but the mechanisms underlying mitochondrial aberrations are still not completely understood. Recent researches have underscored the critical role of calcium signalling in cancer biology, particularly through the mitochondrial calcium uniporter complex (MCUc), which regulates mitochondrial calcium uptake and influences cellular energy, metabolism and apoptosis. However, the specific relationship between the MCUc and ccRCC remains underexplored. This thesis aims to elucidate the functional dynamics of the MCUc in ccRCC by examining its expression levels in human tumor specimens and correlating these findings with the metastatic state of the disease. Additionally, we investigate how manipulation of MCUc stoichiometry affects the invasiveness of renal cell carcinoma cell lines, revealing significant alterations in lipid metabolism and profound changes in mitochondrial morphology and function. By bridging these gaps in knowledge, this research seeks to contribute to a deeper understanding of ccRCC biology and identify potential therapeutic targets for intervention.
Il carcinoma renale a cellule chiare (ccRCC) rappresenta il sottotipo più comune di cancro renale, costituendo circa l'80% dei casi di carcinoma renale negli adulti. La patogenesi del ccRCC è complessa e multifattoriale, con mutazioni nel gene von Hippel-Lindau (VHL) che rappresentano un segno distintivo della malattia. Queste mutazioni interrompono i normali processi cellulari, portando a un'attivazione anomala dei fattori indotti dall'ipossia (HIF) e a conseguenti alterazioni nel metabolismo, nell'angiogenesi e nella proliferazione cellulare. È importante notare che le alterazioni mitocondriali sono una caratteristica comune dei RCC, ma i meccanismi alla base delle anomalie mitocondriali non sono ancora completamente compresi. Ricerche recenti hanno sottolineato il ruolo critico della segnalazione del calcio nella biologia del cancro, in particolare attraverso il complesso del uniporter del calcio mitocondriale (MCUc), che regola l'assorbimento del calcio mitocondriale e influenza l'energia cellulare, il metabolismo e l'apoptosi. Tuttavia, la relazione specifica tra MCUc e ccRCC rimane poco esplorata. Questa tesi si propone di chiarire le dinamiche funzionali del MCUc nel ccRCC esaminando i suoi livelli di espressione in campioni tumorali umani e correlando questi risultati con lo stato metastatico della malattia. Inoltre, investigiamo come la manipolazione della stechiometria dell'MCUc influisca sull'invasività delle linee cellulari di carcinoma renale, rivelando significative alterazioni nel metabolismo lipidico e profondi cambiamenti nella morfologia e funzione mitocondriale. Colmando queste lacune nella conoscenza, questa ricerca mira a contribuire a una comprensione più profonda della biologia del ccRCC e a identificare potenziali bersagli terapeutici per l'intervento.
THE ROLE OF THE MITOCHONDRIAL CALCIUM UNIPORTER COMPLEX IN CLEAR CELL RENAL CELL CARCINOMA PROGRESSION
DHAOUADI, NADA
2025
Abstract
Abstract Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of kidney cancer, accounting for approximately 80% of renal cell carcinoma cases in adults. The pathogenesis of ccRCC is intricate and multifactorial, with mutations in the von Hippel-Lindau (VHL) gene being a hallmark of the disease. These mutations disrupt normal cellular processes, leading to aberrant activation of hypoxia-inducible factors (HIFs) and subsequent alterations in metabolism, angiogenesis, and cell proliferation. Importantly, mitochondrial alterations are a common feature of RCCs, but the mechanisms underlying mitochondrial aberrations are still not completely understood. Recent researches have underscored the critical role of calcium signalling in cancer biology, particularly through the mitochondrial calcium uniporter complex (MCUc), which regulates mitochondrial calcium uptake and influences cellular energy, metabolism and apoptosis. However, the specific relationship between the MCUc and ccRCC remains underexplored. This thesis aims to elucidate the functional dynamics of the MCUc in ccRCC by examining its expression levels in human tumor specimens and correlating these findings with the metastatic state of the disease. Additionally, we investigate how manipulation of MCUc stoichiometry affects the invasiveness of renal cell carcinoma cell lines, revealing significant alterations in lipid metabolism and profound changes in mitochondrial morphology and function. By bridging these gaps in knowledge, this research seeks to contribute to a deeper understanding of ccRCC biology and identify potential therapeutic targets for intervention.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/202960
URN:NBN:IT:UNIVPM-202960