Role of metabolism and mitochondrial function for stem cell differentiation and stress responses upon genotoxic noxae

Background: Metabolic adaptations and alterations in mitochondrial function are important both for achieving pluripotency of stem and progenitor cells (SCs/PCs) and for their differentiation. Mitochondria represent a central switch point in this process, since these metabolic changes and the formation of ROS are decisive for whether cells differentiate or remain pluripotent. Mitochondrial DNA and various functions of mitochondria are impaired by genotoxic substances. The degradation of damaged mitochondria by mitophagy, an important part of mitochondrial quality control (mQC), generally has a protective effect, e.g. against various neurodegenerative diseases and aging, but in excess mitophagy can also have cytotoxic effects.

Aim: How pluripotency, differentiation, metabolism, mitochondrial function and mQC interact and influence each other is of great importance for our understanding of how diseases develop. Overall, we hope to better understand the role of mitochondrial processes in genotoxin-induced modulations of differentiation processes in different cells.

Experimental procedure / working programme: In this project, the differentiation process of mESCs to endothelial cells and to cardiomyocytes after application of genotoxic noxious agents is to be investigated. In particular, we will elucidate the influence of various forms of mitochondrial dysfunction and changes in mitochondrial metabolism. The influence of altering mitochondrial function on differentiation, on properties of differentiated cells (endothelium vs. cardiomyocytes), and the expression of stem cell markers will be investigated. Markers of DNA damage and repair will be quantified in parallel. We plan to determine to which extent mitochondrial quality control pathways have been activated in the different cell types and to what extent toxicity to the genotoxic substances is increased or decreased. A second focus is to clarify whether modulation of energy metabolism influences the sensitivity of mESCs and differentiated cells to sublethal genotoxic noxious agents.

Recent publications:

1. Jahn, S. K., Hennicke, T., Kassack, M. U., Drews, L., Reichert, A. S., and Fritz, G. (2020) Distinct influence of the anthracycline derivative doxorubicin on the differentiation efficacy of mESC-derived endothelial progenitor cells. Biochim Biophys Acta Mol Cell Res 1867, 118711
2. Lu, K., Zimmermann, M., Gorg, B., Bidmon, H. J., Biermann, B., Klocker, N., Haussinger, D., and Reichert, A. S. (2019) Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes. EBioMedicine 48, 539-553
3. Zimmermann, M., and Reichert, A. S. (2017) How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways. Biol Chem 399, 29-45