Role of PEX5 in pexophagy and mitophagy regulation

Peroxisomes are remarkably dynamic organelles that have recently moved into the spotlight of cell biology, biomedical research, and biotechnology. Their function can differ substantially across different species, life stages, and environmental conditions. However, they are predominantly known for their role in the metabolism of lipids and hydrogen peroxide (H2O2). In order to regulate peroxisome function in response to changing nutritional and environmental stimuli, new organelles need to be formed and superfluous and dysfunctional organelles have to be selectively removed. Over the years, it has become increasingly clear that mammalian peroxisomes are mainly degraded by the autophagy-lysosome pathway, in a process known as pexophagy. Emerging evidence suggests that not only defects in peroxisome biogenesis, but also disturbances in pexophagy contribute to disease. Unfortunately, fundamental knowledge about the molecular triggers and signaling pathways behind pexophagy in mammals is still largely lacking. This project is intended to fill this gap by exploring the following interrelated issues: (i) the reciprocal crosstalk between peroxisomal/mitochondrial dysfunction, general autophagy, and organelle turnover (ii) the role of peroxisome-derived H2O2 as signaling messenger in pexophagy, and (iii) the critical factors and mechanisms underlying the role of ubiquitin-PEX5 in peroxisome quality control. As defects in pexophagy appear to be associated with disturbances in cellular redox homeostasis, the outcome of this research is of fundamental importance to our understanding of how dysfunctional pexophagy may act as a driver of cell senescence, organismal aging, and oxidative stress-related pathologies.