The mitochondrial phospholipid cardiolipin (CL) affects mitochondrial biogenesis, morphology / structure, and function. Recent data associate the CL composition with the proliferation of T-lymphocytes.
Tafazzin is an acyl-transferase of outstanding importance in CL remodeling, which significantly influences mitochondrial respiration / ATP production (OXPHOS) and mitochondrial genesis / release of ROS. Mutations in the tafazzin-encoding gene, TAZ, are the cause of the severe X-linked genetic disease, BARTH syndrome (BTHS). There is an association with muscular phenotypes (including dilated cardiomyopathy) because of important limitations of the mitochondrial respiratory chain and OXPHOS. In addition to the expected changes in CL composition and OXPHOS, the genetic manipulation of TAZ expression also causes substantial changes in mitochondrial structure, membrane fluidity and size distribution as well as in proliferation and gene expression.
How the limitation of CL remodeling affects the inhibition of cell proliferation resulting from the "knock-down" or "knock-out" of TAZ is currently unknown. Alterations in the CL composition caused by the knock-down of TAZ inhibit the proliferation of C6 glioma cells. In contrast, similar changes caused by the knock-down of CL synthase do not inhibit proliferation. This observation leads to the hypothesis that TAZ, independent of its function in CL remodeling, can regulate cellular functions and in particular proliferation. The verification of this hypothesis and the elucidation of the responsible mechanisms (in particular the determination of the role of ROS, redox-regulated signaling pathways and metabolism) are current and central issues. These issues are investigated and collaborated across projects in subproject C2 of the GRK1947 / 1 BiOx.
Atrial fibrillation (AF) leads to morphological alterations of the atrial tissue (structural remodeling), which manifests itself in cellular (hypertrophy, atrial obesity), but also in the intercellular substance (interstitial fibrosis, amyloidosis). These changes influence the electrophysiological as well as the mechanical functions of the atria. Even short episodes of AF cause furthermore an activation of the atrial endocardium and the endothelium (endocardial / endothelial remodeling). A central pathogenetic importance is the dysregulation of the local renin-angiotensin system. Increased formation of angiotensin II (AngII) and angiotensin II receptor type I (AT1R) -mediated signal transduction, including initiation of oxidative stress, have been identified as major causes of AF development and progression. Recent data show that a local protective cardiac axis of the RAS (ACE2 / Ang- (1-7) / Mas) can counteract the classical RAS (ACE / AngII / AT1R). The contribution of these RAS axes to atrial remodeling and in particular to the differentiation of epicardium-derived progenitor cells (EPDCs) into atrial adipocytes and fibroblasts is currently being investigated in the Lendeckel / Wolke research group.
Another focus of the working group is the functional examination of the ectopeptidase membrane alanyl aminopeptidase (EC3.4.11.2, CD13, APN) regarding the pathogenesis of cardiovascular, autoimmune and inflammatory diseases and diabetes.
The priority objective of current projects is the elucidation of the molecular mechanisms underlying the effects resulting from the "knock-out" or the pharmacological inhibition of APN / CD13. These effects include:
