Project Details
Projekt
Redox control of ER-mitochondria communication: Implications for melanoma pathobiology
Subject Area
Anatomy and Physiology
Biochemistry
Biochemistry
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 545970076
Organelle architecture, dynamics and inter-compartmental signaling are essential parameters that govern many cellular functions. In cancer cells the organelle communication is altered, mainly to support metabolic changes that control malignant cell growth and metastatic dissemination. The mitochondria-ER contact sites (MERCs) in particular have been described as key regulators of carcinogenesis, cancer cell pathobiology, and progression. Among other processes, MERCs are involved in controlling cellular redox state. However, the effects of redox regulation on the MERC architecture and function is not understood, mainly due to the lack of appropriate experimental tools. With this project proposal, we aim to identify molecular players involved in the redox regulation of MERCs and develop tools that will allow a precise functional evaluation of the ER-mitochondria communication. Concretely, we will identify and characterize redox sensitive residues in MERC constituents such as VAPB and GRP75. Using genetic manipulations and various imaging techniques, we will evaluate the impact of redox regulation on MERC structure and function. By generating novel organelle-targeted and light-activated calcium cages, as well as fluorescently labelled Coenzyme Q10 derivatives, we will provide novel tools for investigating the functional implications of MERC redox regulation. Ultimately, genetic manipulations, transcriptome and proteome screens, and bioinformatic analyses will be applied to understand the impact of MERC redox regulation in melanoma aggressive behavior and therapeutic sensitivity. In detail, we are planning to address the following aims: (1) Identify and characterize thiol switches in MERC constituting proteins (MERCcps). (2) Generate new tools to examine the influence of MERC redox regulation on Ca2+ and lipid transfer. (3) Examine the influence of redox regulation on MERC architecture. (4) Investigate the role of MERC redox regulation in melanoma cell pathobiology.
DFG Programme
Research Grants
