Project Details
Projekt
Unraveling metabolic signaling in podocytes and its contribution to FSGS
Subject Area
Nephrology
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 386793560
Mitochondria in addition to their classical function as cellular power plants have recently been recognized as central signaling hubs to control metabolic signaling pathways. Inspired by a cluster of nuclear gene mutations known to cause inherited SRNS which affect mitochondrial proteins and in particular co-enzyme Q10 biosynthesis, we comprehensively analyzed the primary sources of energy of glomerular podocytes within the first funding period. Interestingly, podocytes maintain their metabolic balance under physiological conditions primarily via anaerobic glycolysis independent of the oxidative phosphorylation (OXPHOS) machinery. These findings challenge our view on mitochondrial function in podocytes. Recently, we described a novel link between mitochondrial function and insulin signaling in podocytes: an impairment of the mitochondrial fusion and fission machinery caused by loss of the expression of the mitochondrial proteins OMA1 or PHB2 resulted in an overactivation of the insulin signal cascade comprising AKT and the nutrient-sensor mTOR. The overarching goal of this project is to gain mechanistic insights into the role of deregulated mitochondrial signaling and subsequent metabolic consequences in the pathogenesis of FSGS. For this purpose, we will (Aim 1) delineate the metabolic impact of dysfunctional mitochondria employing Oma1 and Phb2 deficient podocytes both, in vitro and in vivo. We will perform extensive metabolomic and proteomic analyses as well as functional assays to understand the specific contributions of insulin and mTOR signaling. In an independent approach (Aim 2), we will focus on the mitochondrial gene cluster known to cause inherited SRNS and we will systematically study the impact of co-enzyme Q10 biosynthesis in podocytes and the role in FSGS. We make use of our newly established mouse models resembling the human disease to unravel podocyte-specific co-enzyme Q10 signaling networks by a comprehensive analysis of the metabolome, proteome and ultimately transcriptome (Aim 2). Finally (Aim 3), we will translate our findings to renal biopsies of patients with MCD/FSGS collected in the FOrMe registry. Here, we will employ a novel unbiased MS/MS based approach using glomerular tissue from paraffin embedded sections of human kidney biopsies as well as a targeted approach to go deeper into metabolic signaling. Additional targeted approaches will allow us to focus on the contribution of metabolic signaling pathways among others.
DFG Programme
Clinical Research Units
