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Peroxisome Interactions and Communication

Periodic Reporting for period 2 - PERICO (Peroxisome Interactions and Communication)

Reporting period: 2020-10-01 to 2023-03-31

PERICO aimed to train a new generation of highly qualified ESRs with entrepreneurial competencies in the field of Molecular Life Sciences through state-of-the-art research projects focusing on the identification and functional characterization of peroxisomal contact sites, their functions and regulation. Peroxisomes are cell organelles that occur in almost all eukaryotes and play key roles in metabolism. Common peroxisome functions are the degradation of fatty acids and hydrogen peroxide. Specialized functions include bile acid biosynthesis in mammals, photorespiration in plants, penicillin biosynthesis in filamentous fungi and, as glycosomes, glycolysis in Trypanosomae. Peroxisomes also fulfil crucial non-metabolic roles, e.g. in stress response, cellular signalling and ageing.
From their diversity of functions, peroxisomes cannot function in isolation but rather must communicate and interact extensively with their environment to exchange metabolites and coordinate cellular responses. Membrane contact sites, where membranes of two organelles are physically tethered to enable rapid transfer of small molecules, enable organelle communication and are crucial for coordination of cellular functions and hence human health. Often, at these contact sites there is an accumulation of transport proteins that enable rapid and regulated metabolite exchange.
The knowledge generated in the PERICO network can be used to develop novel leads for drug discovery and therapies for a growing list of serious human diseases in which peroxisomes have been implicated such as age-related disorders, metabolic disorders (including severe malnutrition on the one hand and obesity on the other) and pathogenic trypanosomal infections (e.g. sleeping sickness), where glycosomal contact sites are attractive novel targets for drug design.
The main aims of PERICO were:
I. To understand the role of physical contacts between peroxisomes and other organelles in controlling cellular metabolism
II. To characterize the role of peroxisomal transporter proteins in cellular metabolism
III. To understand the significance of peroxisome communication in health and disease
Using a combination of bioinformatics and experimental approached novel putative peroxisomal contact site resident proteins and transporters were identified in mammals, yeast and trypanosomes. The bioinformatics approaches included the development of machine learning-based predictors. The experimental approaches included in vivo and in vitro pull down experiments and proximity ligation assays followed by protein identification using mass spectrometry. Novel peroxisomal proteins were also identified by mass spectrometry analysis of purified peroxisomal membranes as well as by advanced high throughput fluorescence microscopy screens in yeast. The most promising candidate proteins were validated and further analysed. These approaches resulted in the identification of several peroxisomal membrane contact site resident proteins and transporters in yeast, human and trypanosomes. Cell lines, yeast libraries, plasmids, data sets and predictors were generated, which are available for exploitation. The newly identified human and trypanosomal proteins can potentially be exploited as novel drug targets.
Since PERICO addressed health problems like metabolic disorders, age-related diseases and trypanosomiasis, it was of great benefit for European industrial competitiveness and to the society. PERICO has contributed to maintaining the leading position of European research within the field of cellular metabolism and inter-organelle communication, with direct implications on medical and biotechnological applications. PERICO provided important contributions to the strengthening of European innovation capacity, through the close public-private sector collaboration.