| dc.description.abstracteng | 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. | de |