Unravelling the role of the mitochondrial CLPXP complex in protein quality control, aging and development of Podospora anserina

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The biological role of the mitochondrial CLPXP, a protease complex located in the mitochondrial matrix, is currently unsufficiently understood. In yeast, CLPP is missing but CLPX is implicated in a number of mitochondrial pathways (e.g. mitochondrial genome maintenance). In Caenorhabditis elegans CLPXP is involved in UPRmt, in mammals, its role in this process is controversially discussed. However, in a recent study a function of CLPP in the control of the energy metabolism related to acute myeloid leukemia was reported. In an approach towards the functional characterization of this poorly characterized protein complex, we identified a number of potential substrates and interaction partners in the fungal aging model Podospora anserina. The identified proteins strongly support a role of PaCLPXP in the control of cellular energy metabolism. Moreover, we found that ablation of PaCLPXP components results in an increased lifespan and a robust induction of autophagy. The main focus of the proposed renewal of this research project is the elucidation of the molecular mechanisms leading to autophagy induction and in particular the role of PaCLPXP in the control of this process. Based on our recent findings, we will (i) search for and characterize potential transcriptional regulators which are involved in PaCLPXP-dependent mitochondria-to-nucleus signaling and (ii) will study selected substrates and interaction partners of PaCLPXP. More specifically, we will analyze the role of candidate transcription factors identified as differentially expressed in a transcriptome analysis of the P. anserina wild type and the PaClpP deletion strain. In addition, we will study the role of PaCLPXP in controlling the cellular energy metabolism via the analysis of the activity of key enzymes and of the abundance of relevant metabolites in the wild type and PaClpXP mutants. From these investigations we expect important new exciting information about the biological function of mitochondrial CLPXP in the complex cellular network controlling cellular homeostasis that is of utmost importance for correct development and a long healthy lifespan of biological systems.