Prof. Frank Edlich, head of the Biochemistry group, and his colleagues are investigating the cellular regulation of apoptosis, the most common form of cell death. This important physiological process is the center of important questions.
Regulation of mitochondrial apoptosis
Apoptotic cells remove themselves and thereby protect their multicellular organism from serious pathologies, such as tumor diseases. Apoptotic cells shrink and form apoptotic vesicles into which they pack their contents for complete removal by phagocytosis. Apoptosis can be induced either by signals (death receptor ligands) at the cell surface or by cell stress. In both cases, BCL-2 family proteins play central roles in signal integration and the molecular decision between regulated suicide by apoptosis and survival.
This decision takes place at the outer membrane of mitochondria. In this process, the pro-apoptotic BCL-2 BAX and the very similar BAK have a special function. Activation of both proteins leads to the initiation of a signaling cascade of caspases, proteases whose activity irreversably commits a cell to apoptosis. Therefore, activation of BAX and BAK is the molecular decision to apoptosis. Active BAX/BAK can permeabilize the outer mitochondrial membrane so that intermembrane space proteins, such as cytochrome c, are released. This release causes an interruption of mitochondrial respiration and, the formation of the apoptosome to activate caspase-9. Although the central importance of BAX/BAK activation not only for the prevention but also the therapy of tumor diseases and other severe pathologies is undisputed, this important physiological process is the center of important questions.
Our laboratory is mainly concerned with the following questions:
- How are BAX and BAK regulated in cells depending on cell stress and stress response?
- How do inhibition and activation of BAX and BAK work?
- Can we predict whether a therapy will activate BAX and BAK in target cells?
- Are there ways to circumvent the cell-intrinsic regulation of BAX and BAK?
- How do BAX and BAK activate caspases?
- Jayavelu AK, Schnöder TM, Perner F, Herzog C, Meiler A, Krishnamoorthy G, Huber N, Mohr J, Edelmann-Stephan B, Austin R, Brandt S, Palandri F, Schröder N, Isermann B, Edlich F, Sinha AU, Ungelenk M, Hübner CA, Zeiser R, Rahmig S, Waskow C, Coldham I, Ernst T, Hochhaus A, Jilg S, Jost PJ, Mullally A, Bullinger L, Mertens PR, Lane SW, Mann M, Heidel FH. Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature. 2020 Dec; 588(7836):157-163. doi: 10.1038/s41586-020-2968-3.
- Funk K, Czauderna C, Klesse R, Becker D, Hajduk J, Oelgeklaus A, Reichenbach F, Fimm-Todt F, Lauterwasser J, Galle PR, Marquardt JU, Edlich F. BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC. Cancers. 2020 May;12(6):1437. doi: 10.3390/cancers12061437.
- Cakir Z, Funk K, Lauterwasser J, Todt F, Zerbes RM, Oelgeklaus A, Tanaka A, van der Laan M, Edlich F. Parkin promotes proteasomal degradation of misregulated BAX. J Cell Sci. 2017 Sep;130(17):2903-2913. doi: 10.1242/jcs.200162.
- Reichenbach F, Wiedenmann C, Schalk E, Becker D, Funk K, Scholz-Kreisel P, Todt F, Wolleschak D, Döhner K, Marquardt JU, Heidel F, Edlich F. Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML. Clin Cancer Res. 2017 Aug; 23(16):4805-4816. doi: 10.1158/1078-0432.CCR-16-1941.
- Andreu-Fernández V, Sancho M, Genovés A, Lucendo E, Todt F, Lauterwasser J, Funk K, Jahreis G, Pérez-Payá E, Mingarro I, Edlich F, Orzáez M. Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes. Proc Natl Acad Sci U S A. 2017 Jan; 114(2):310-315. doi: 10.1073/pnas.1612322114. Erratum in: Proc Natl Acad Sci U S A. 2017 Feb; 114(8):E1574.
- Lauterwasser J, Todt F, Zerbes RM, Nguyen TN, Craigen W, Lazarou M, van der Laan M, Edlich F. The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Sci Rep. 2016 Sep; 6:32994. doi: 10.1038/srep32994.
- Todt F, Cakir Z, Reichenbach F, Emschermann F, Lauterwasser J, Kaiser A, Ichim G, Tait SW, Frank S, Langer HF, Edlich F. Differential retrotranslocation of mitochondrial Bax and Bak. EMBO J. 2015 Jan; 34(1):67-80. doi: 10.15252/embj.201488806.
- Todt F, Cakir Z, Reichenbach F, Youle RJ, Edlich F. The C-terminal helix of Bcl-x(L) mediates Bax retrotranslocation from the mitochondria. Cell Death Differ. 2013 Feb; 20(2):333-42. doi: 10.1038/cdd.2012.131.
- Edlich F, Banerjee S, Suzuki M, Cleland MM, Arnoult D, Wang C, Neutzner A, Tjandra N, Youle RJ. Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell. 2011 Apr 1;145(1):104-16. doi: 10.1016/j.cell.2011.02.034.
- Hoppins S, Edlich F, Cleland MM, Banerjee S, McCaffery JM, Youle RJ, Nunnari J. The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. Mol Cell. 2011 Jan 21;41(2):150-60. doi: 10.1016/j.molcel.2010.11.030.