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Peroxisome Interactions and Communication

Periodic Reporting for period 1 - PERICO (Peroxisome Interactions and Communication)

Reporting period: 2018-10-01 to 2020-09-30

PERICO aims 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, it is clear that 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. Research on contact sites is a challenging, upcoming field in current cell biology.
The knowledge generated in the PERICO network will 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 are:
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 have been identified in mammals, yeast and trypanosomes. The bioinformatics approaches include a newly developed machine learning-based predictor. Candidate proteins are also identified based on literature data. The experimental approaches include 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 using mass spectrometry analysis of purified peroxisomal membranes as well as by advanced high throughput fluorescence microscopy screens in yeast. The most promising candidate proteins are currently validated and further analysed.
Since PERICO addresses health problems like metabolic disorders (e.g. diabetes mellitus, malnutrition), age-related diseases (such as neurodegenerative diseases and cancer) and trypanosomiasis, etc. it will be of great benefit for European industrial competitiveness and to the society. PERICO will help to maintain the leading position of European research within the field of cellular metabolism and inter-organelle communication, with direct implications on medical, biotechnological and agricultural applications, which will benefit European industrial competitiveness. PERICO will provide an important contribution to the strengthening of European innovation capacity, through the close public-private sector collaboration, including high-tech SMEs and large companies. The PERICO network aims to sustain itself after the end of the project both for research collaboration and for long lasting, future training of inter-disciplinary young researchers and PhD students.