The mitochondrial phospholipid cardiolipin (CL) influences mitochondrial biogenesis, morphology / structure and function. Recent data associate CL composition with T lymphocyte proliferation.
Tafazzin is an acyltransferase of outstanding importance in CL remodeling, which significantly influences mitochondrial respiration / ATP production (OXPHOS) and the mitochondrial formation / release of ROS. Mutations in the Tafazzin-coding gene, TAZ, are the cause of the severe X-linked genetic disease, BARTH syndrome (BTHS). This is associated with muscular phenotypes (including dilated cardiomyopathy) due to the considerable limitations of the mitochondrial respiratory chain and OXPHOS.
In addition to the expected changes in the 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 proliferation and gene expression.
What contribution the restriction of CL remodeling makes to the inhibition of cell proliferation resulting from the “knock-down” or “knock-out” of TAZ is currently not known. Changes in the CL composition caused by the knock-down of TAZ inhibit the proliferation of C6 glioma cells. In contrast, similar changes of CL composition, if they are caused by the "knock-down" of CL synthase, do not inhibit proliferation.
This observation leads to the hypothesis that TAZ can regulate cellular functions and especially proliferation, regardless of its function in CL remodeling. 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 questions that are being dealt with within the framework of a Bogislaw scholarship.
Atrial fibrillation (AF) leads to morphological alterations of the atrial tissue (structural remodeling), which manifest themselves at the cellular level (hypertrophy, atrial obesity), but also in the intercellular substance (interstitial fibrosis, amyloidosis). In addition to the electrophysiological changes, these changes also affect the mechanical functions of the auricles. Even short episodes of AF also activate the atrial endocardium and the endothelium (endocardial / endothelial remodeling). Short episodes of AF, interrupted by recovery phases in sinus rhythm, produce an atrial phosphorylation pattern (phosphoproteome) that is substantially different from that produced by longer continuous AF episodes. Kinases differentially expressed / phosphorylated under both AF conditions are currently being investigated functionally and with regard to their pathophysiological relevance in the Lendeckel / Wolke group.
Another focus of the working group is the elucidation of the function of the ectopeptidase membrane alanyl aminopeptidase (EC3.4.11.2, CD13, APN) for the pathogenesis of cardiovascular, autoimmune and inflammatory diseases, diabetes and tumors. 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:
The Renin Angiotensin System (RAS) is associated with glucose homeostasis in a number of ways. The activation of the RAS and the resulting increased plasma concentrations of AngII cause insulin resistance in muscle and adipose tissue. In addition to the induction of insulin resistance, the effect of increased AngII levels is also associated with the impairment of the β-cell function and thus the adequate production / secretion of insulin.
Beneficial effects of the alternative RAS axis ACE2 / Ang- (1-7) / Mas with regard to glucose homeostasis are described, but mainly relate to the improvement of insulin sensitivity and thus glucose uptake in peripheral tissue (muscle, adipose tissue). We have already been able to show that Ang-(1-7) also increases glucose-stimulated insulin secretion (GSIS) (Sahr et al.).
As part of a project funded by the DFG (Le/13-1), the responsible receptors (Mas and / or MrgD) are now to be identified and, in addition, the extent to which Ang- (1-7) and / or related agonists represent a new and very promising strategy for the treatment of diabetes mellitus, in that, in addition to improving the peripheral insulin resistance, they also restore the-cell-associated function, namely the adequate GSIS by stimulating the regeneration of functional β cells.
no news in this list.
