Pathophysiological role of pyrroline-5-carboxylate synthase (P5CS) in cutis laxa with progeroid features

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Aging leads to a progressive decline of tissue function due to the accumulation of damaged cells and cell loss. Through apoptosis regulation and as a source of oxidative stress mitochondria are a major player in this process. Segmental progeroid disorders like cutis laxa caused by mutations in pyrroline-5-carboxylate reductase 1 (PYCR1) and pyrroline-5-carboxylate synthase (P5CS) recapitulate aspects of chronological human aging. Both gene products a part of the mitochondrial proline cycle, but how disturbance of this metabolic pathway leads to this characteristic phenotype is still incompletely understood. The aim of the proposed project is to further investigate the role of the P5CS enzyme in a physiological and pathophysiological context. We recently described de novo mutations leading to subtle changes in sub-mitochondrial distribution and the biochemical behavior of the P5CS protein complex. Different in vitro approaches will be used to investigate the targeting of this enzyme to its destination within the mitochondria. Furthermore, Complexome profiling and immunoprecipitation will be used to gain knowledge about the P5CS protein complex. Additionally, the metabolic flux through the proline cycle and connected metabolic pathways will be investigated using metabolomics. To complement these in vitro approaches, we will investigate a mouse model with different degrees of P5CS dysfunction. This will provide detailed insights into the tissue changes of P5CS-related cutis laxa at a histological, ultrastructural, and molecular level. These model will also allow to verify in vivo the identified alterations of the proline cycle and connected metabolic pathways. This will clarify which alterations are the cause of the observed cutis laxa phenotype.Our study will allow for a deeper understanding of the pathophysiological situation in P5CS-related cutis laxa and will provide the basis for future treatment strategies. It will furthermore help to clarify how the proline cycle influences mitochondrial function and the normal aging processes.