Exploring the role of peroxisome-derived hydrogen peroxide in the physiology of mammalian cells

Mammalian cells are fine-tuned dynamic systems that rely on redox-driven changes to regulate diverse physiological processes, such as cell proliferation and differentiation. High intracellular concentrations of reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are traditionally associated with cell damage and disturbances in redox homeostasis, which represent a hallmark of disease (e.g., cancer). However, low concentrations of H2O2 may function as a signaling agent, mainly through the oxidation of redox-sensitive cysteine residues in various classes of target proteins (e.g., transcription factors, phosphatases, antioxidant enzymes). Thus far, a large panel of H2O2-sensitive proteins has been identified. Nonetheless, most of these targets have been identified by applying exogenous H2O2, a condition rarely mimicking the physiological situation. In mammals, H2O2 is produced in different subcellular locations, including peroxisomes. These organelles essentially participate in the metabolism of lipids and ROS, and in particular H2O2. To date, peroxisomes are also increasingly appreciated as an important redox signaling platform, as their dysfunction is associated to a panel of oxidative stress-related disorders. The overall aim of this project is to gain more insight into how alterations in peroxisomal H2O2 metabolism influence the physiology of mammalian cells. By using a human cell model in which peroxisome-derived H2O2 can be controlled in a time- and dose-dependent manner, we will (1) inventorize its protein thiol targets, (2) study its role in retrograde signaling, and (3) investigate how it affects mitochondrial biology. Finally, we will validate the in cellulo findings in more disease-related cell types and tissues from control mice and mice suffering from peroxisomal deficiencies. Where applicable, we will focus on the potential role of peroxisome-derived H2O2 in cancer.