Peroxisomes in Health and Disease

Peroxisomes are dynamic organelles that play essential roles in lipid metabolism, the detoxification of reactive oxygen species, and cellular signaling. In mammalian cells, they also function as important hubs for redox regulation, lipid homeostasis, innate immunity, and antiviral defense. Consequently, the biogenesis and maintenance of the peroxisomal proteome, together with communication between peroxisomes and other organelles, are critical for cellular functions and disease.

Our research aims to understand how functional peroxisomes are formed, maintained, and integrated into the cellular organelle network, and how their dysfunction contributes to human disease. We combine subcellular and structural proteomics, cell biology, biochemistry, high-resolution mass spectrometry and computational approaches to investigate fundamental mechanisms of peroxisome biogenesis, dynamics and function.

A major focus of our work is the biogenesis of peroxisomes and the mechanisms that mediate the import of peroxisomal matrix proteins in yeast and human cells. These proteins are synthesized in the cytosol and imported post-translationally through translocation pores in the peroxisomal membrane in a receptor-mediated process.

Using functional proteomics and biochemical approaches, we have characterized central peroxisomal import complexes, providing detailed insights into their composition, stoichiometry, regulation, and molecular architecture. Among our key discoveries is the identification of the novel peroxisome biogenesis factor PEX39, which stabilizes receptor-cargo complexes and facilitates their handover to the peroxisomal docking and translocation machinery. Our current work combines structural proteomics with functional analyses to obtain a molecular understanding of the dynamic assembly of peroxisomal import complexes and the mechanisms that govern protein translocation into the organelle.

We have also identified and characterized ER-peroxisome contact site (EPCON) proteins, uncovering an important functional link between organelle contact sites and peroxisomal lipid metabolism. Ongoing research investigates the roles of previously unrecognized dual localized peroxisomal proteins in the formation and regulation of peroxisomal contact sites with other organelles, including the ER and mitochondria.

Another major research focus is the comprehensive characterization of the human peroxisomal proteome. This remains technically challenging because peroxisomes are low-abundance organelles, and many peroxisomal proteins are shared with other cellular compartments, including the cytosol, mitochondria, and the ER.

To overcome these challenges, we established a deep spatial subcellular proteomics approach specifically optimized for peroxisomes. By combining state-of-the-art high-resolution spectrometry with machine learning, we can determine the subcellular localization of more than 10,000 proteins across the human proteome. Candidate peroxisomal proteins are validated through interactome analyses, fluorescence microscopy, and protein-specific functional assays.

This resource provides a foundation for understanding peroxisome biology in health and disease. We are now extending these studies to investigate the dynamics of the human peroxisomal proteome and to determine how the loss of peroxisomes reshapes the cellular proteome and impacts proteostasis.

Peroxisomes are increasingly recognized as important regulators of innate immunity and antiviral defense. In a new line of research, we investigate how viral infections remodel the peroxisomal proteome and alter protein abundance and localization throughout the cell.

Our goal is to identify host proteins that are recruited to or displaced from peroxisomes during infection, determine how these changes affect peroxisomal metabolism and antiviral signaling, and distinguish conserved from or virus-specific mechanisms of peroxisome remodeling. By combining dynamic spatial proteomics and machine learning with functional studies, we generate time-resolved maps of virus-induced remodeling of the peroxisomal and extra-peroxisomal proteomes, providing new insights into the role of peroxisomes in virus–host interactions.