MCU controls melanoma progression through a redox‐controlled phenotype switch

2022 | journal article. A publication with affiliation to the University of Göttingen.

Jump to:Cite & Linked | Documents & Media | Details | Version history

Cite this publication

​MCU controls melanoma progression through a redox‐controlled phenotype switch​
Stejerean‐Todoran, I.; Zimmermann, K.; Gibhardt, C. S.; Vultur, A.; Ickes, C.; Shannan, B. & Bonilla del Rio, Z. et al.​ (2022) 
EMBO reports23(11).​ DOI: 

Documents & Media

EMBR_EMBR202254746.pdf5.2 MBAdobe PDF


Published Version

Attribution 4.0 CC BY 4.0


Stejerean‐Todoran, Ioana; Zimmermann, Katharina; Gibhardt, Christine S.; Vultur, Adina; Ickes, Christian; Shannan, Batool; Bonilla del Rio, Zuriñe; Wölling, Anna; Cappello, Sabrina ; Sung, Hsu‐Min; Shumanska, Magdalena; Zhang, Xin; Nanadikar, Maithily; Latif, Muhammad U.; Wittek, Anna; Lange, Felix; Waters, Andrea; Brafford, Patricia; Wilting, Jörg ; Urlaub, Henning ; Katschinski, Dörthe Magdalena ; Rehling, Peter ; Lenz, Christof ; Jakobs, Stefan ; Ellenrieder, Volker; Roesch, Alexander; Schön, Michael Peter ; Herlyn, Meenhard; Stanisz, Hedwig; Bogeski, Ivan 
Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The MCU complex is a major route for calcium into the mitochondrial matrix but whether MCU affects melanoma pathobiology was not understood. Here, we show that MCUA expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor‐resistant melanomas. Knockdown (KD) of MCUA suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCUA_KD reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCUA and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCUA_KD‐induced invasive phenotype. Furthermore, MCUA_KD increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCUA controls melanoma aggressive behavior and therapeutic sensitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with current therapies, should be considered in treating advanced melanoma.
Synopsis image The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma. MCU controls mitochondrial Ca2+ dynamics, production of ROS and ATP in melanoma cells. MCU downregulation hinders melanoma cell growth and stimulates cellular motility and metastasis. Melanoma cells develop increased resistance to immunotherapies and ferroptosis inducers upon MCU downregulation.
The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma. image
Issue Date
EMBO reports 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | P01: Untersuchung der Unterschiede in der Zusammensetzung, Funktion und Position von individuellen MICOS Komplexen in einzelnen Säugerzellen 
SFB 1190 | P13: Protein Transport über den mitochondrialen Carrier Transportweg 
SFB 1190 | P17: Die Rolle mitochondrialer Kontaktstellen im Rahmen tumorrelevanter Calcium- und Redox-Signalwege 
TRR 274: Checkpoints of Central Nervous System Recovery 
Institut für Herz- und Kreislaufphysiologie ; Universitätsmedizin Göttingen ; Klinik für Dermatologie, Venerologie und Allergologie ; Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie ; Max-Planck-Institut für Multidisziplinäre Naturwissenschaften ; Klinik für Neurologie ; Abteilung für Anatomie und Zellbiologie ; Institut für Klinische Chemie ; Institut für Zellbiochemie 
Working Group
RG Bogeski 
RG Jakobs (Structure and Dynamics of Mitochondria) 
RG Rehling (Mitochondrial Protein Biogenesis) 
RG Urlaub (Bioanalytische Massenspektrometrie) 
External URL
Deutsche Forschungsgemeinschaft (DFG)
Saarland University
Open Access funding enabled and organized by Projekt DEAL



Social Media