The role of Mic60 in melanoma disease progression
by Nanouk Kirpal
Date of Examination:2025-11-20
Date of issue:2025-10-22
Advisor:Dr. Ivan Prof Bogeski
Referee:Dr. Ivan Prof Bogeski
Referee:Prof. Dr. Michael Meinecke
Persistent Address:
http://dx.doi.org/10.53846/goediss-11576
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Description:Thesis Nanouk Kirpal_The role of Mic60 in melanoma disease progression
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Abstract
English
This study aimed to enhance understanding of Mic60’s role in cancer, particularly in melanoma. The primary objectives were to assess the impact on mitochondrial ultrastructure and function as well as on basic cellular traits and therapy sensitivity in primary and metastatic melanoma. TEM (transmission electron microscopy) and STED (stimulated emission depletion) microscopy revealed a severely disrupted inner mitochondrial organization, including mitochondrial network fragmentation and disturbed cristae biogenesis and structure. This deterioration was shown to impair mitochondrial ATP production and alter mitochondrial membrane potential in both examined cell lines. In primary melanoma (WM1366), Mic60 downregulation resulted in minor changes in mitochondrial Ca2+ uptake, cytosolic Ca2+ signaling, cell viability and clonogenic potential. However, concerning therapy sensitivity, the Mic60 downregulated cell lines of WM1366 displayed increased sensitivity against targeted therapy with MEK inhibitor Trametinib. In contrast, Mic60 absence in metastatic melanoma (WM3734a) had pronounced effects. In this matter mitochondrial Ca2+ as well as SOCE (store operated calcium entry) and ATP-induced Ca2+ uptake were found to be reduced. Furthermore, Mic60 downregulation diminished proliferation, cell viability and clonogenic potential in WM3734a Mic60kd cell lines. In terms of therapeutic sensitivity, the Mic60 knockdown evoked a declined susceptibility against NK cell mediated killing. Overall, our findings underscore Mic60's central role not only in cristae organization and inner mitochondrial membrane architecture but also in mitochondrial metabolism and ion signaling, proliferation and therapeutic sensitivity. Remarkably, Mic60 appears to be involved beyond intraorganellar processes in phenotype switching, interorganellar signaling and therapeutic sensitivity through its interaction partners in the outer mitochondrial membrane and altered mitochondrial signaling. This implies a role as central cog in mitochondrial reprogramming, cancer metabolism and signaling. However, this study only provides initial insights into Mic60’s role in cancer and raises several questions. Further research could shed light onto the mechanisms involved to understand how Mic60 influences these pathways and how Mic60 modulation in cancer serves mitochondrial reprogramming and disease progression.
Keywords: Mic60; mitochondria; melanoma; cancer; mitofilin; MICOS
