Unveiling the molecular mechanisms to modulate peroxisome dynamics and abundance for improvement of cell performance

Lead Research Organisation: University of Exeter
Department Name: Biosciences

Abstract

One of the hallmarks of eukaryotic cells is the presence of membrane-bound compartments (organelles), which create different optimised environments to promote various metabolic reactions required to sustain life. To adapt to the changing physiological requirements of a cell or organism, organelles have to constantly adjust their number, shape, position, and metabolic functions accordingly. This requires dynamic processes which modulate organelle abundance by organelle formation (biogenesis), degradation (autophagy), or inheritance (cell division). Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently. Our work has revealed that peroxisomes are extremely dynamic and can form from pre-existing organelles in a multistep process which requires remodelling of the peroxisomal membrane, the formation of tubular membrane extensions which subsequently constrict and divide into several new peroxisomes. Defects in peroxisome dynamics and multiplication have been linked to age related disorders involving neurodegeneration, loss of sight and deafness. Despite their fundamental importance to cell physiology, the mechanisms that mediate and regulate peroxisome membrane dynamics and abundance in humans are poorly understood and a biophysical model is missing. Understanding these mechanisms is not only important for comprehending fundamental physiological processes but also for understanding pathogenic processes in disease etiology. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions.
In this research project, we will (1) assess the role of key proteins in peroxisome division to unveil the molecular mechanisms modulating peroxisome abundance, (2) apply biophysical approaches to investigate protein-lipid interaction and membrane remodelling, (3) identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions.
In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with biophysical and mathematical approaches as well as novel tools and models in human cell biology. We will apply molecular cell biology, biophysical, biochemical and screening approaches, mathematical modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. Specifically, this research project will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders. We will generate new tools and models for assessing and modulating organelle dynamics, which may help to improve cell performance. Understanding how to modulate organelle dynamics and abundance and to use the protective functions of organelles will be of significant biological and medical importance. It may contribute to the development of new therapeutic approaches in healthy ageing and age-related disorders.

Technical Summary

In this project we will address fundamental open questions related to the molecular mechanisms and pathways that mediate and regulate organelle dynamics and abundance. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions. Peroxisomes have vital, protective roles in lipid metabolism, signalling, and the combat of oxidative stress, thus influencing developmental and ageing processes. We will now apply novel tools and cellular models to assess and modulate organelle dynamics and abundance, which may improve cell performance in health and disease.
In this project we will (1) combine molecular cell biology, biochemical and microscopic approaches to determine the molecular mechanisms modulating peroxisome membrane dynamics and abundance in humans. We will (2) apply biophysical approaches to investigate membrane remodelling and lipid interaction of key proteins. Furthermore, we will (3) combine screening approaches with physiological studies to identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) apply mathematical and computational modelling to develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions.
This interdisciplinary project applies molecular cell biology, biophysical, biochemical and screening approaches, mathematic modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. It will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders.

Planned Impact

This project seeks to deliver ongoing national and international i) academic, ii) medical, iii) political, iv) economic and v) social impact from multi-disciplinary research by building knowledge around the link between organelle dynamics/abundance, cell performance and dysregulation which may result in disease (i, ii, iii, iv), and by improving understanding of associated proteins, their impact on healthy ageing, age-related disorders and diagnostics (i, ii, iv, v). By focusing on the topic of organelle dynamics and regulation of organelle abundance, its findings are highly relevant given the current importance of cellular redox balance and lipid/energy regulation in maintaining normal cellular homeostasis and in the ageing process. In the longer term, this new knowledge will also help inform on risk factors for the initiation and progression of common, age-related diseases such as obesity, diabetes, cardiovascular disease, neurodegeneration and cancer. The research proposed is novel and highly important to aid our understanding of how organelle dynamics and multiplication impact on normal and disease processes; it is therefore envisaged that this work will be beneficial for academics and clinicians as well as health professionals, charitable bodies and others engaged with health promotion by enhancing quality of life, health, wellbeing and healthy ageing. The work aims to understand fundamental processes in human cell biology, organelle biogenesis and cell physiology which have the potential to impact upon developments within both the biological and medical research communities and could enable the identification of new drugs and approaches to modulate organelle dynamics, which may help to improve cell performance in health and disease. This in turn has the potential to benefit understanding of healthy ageing, degenerative and other age-related diseases with the potential to be exploited in both the pharmacological and public health sectors. The fusion of multiple disciplines that constitutes this work will help to highlight to the general community the potential benefits of systems-led and inter- and multi-disciplinary research that UKRC are championing. The reason for this potential is that the mechanisms of organelle dynamics and regulation of abundance are poorly understood, but are essential for cellular viability and development of the organism. An additional outcome of this research will be the development of new tools and models for assessing and modulating organelle dynamics to improve cell performance in health and disease, which will be of benefit to the scientific community as a whole and impact on the development of both biological and medical science in this field.
Through cooperation with industry (Novatis, CH) this research has potential impact on the identification of drugs and the development of novel therapeutic approaches for healthy ageing and treatment of age-related disorders (of benefit to the UK and European pharmaceutical and health sectors) as well as in the diagnosis of pathophysiological conditions and disorders (public health sector). The project team and the University of Exeter's (UoE) Innovation, Impact and Business Team (UoE IIB) have established networks of industry contacts, and research findings will be formally reviewed annually, to explore and coordinate links with business and key project partners. The UoE has excellent links with the wider public with regular events with contributions from research staff. Researchers make regular school visits to explain their research and run events as part of National Science week. Programmes such as this and other outreach activities are critical for the long-term maintenance of the UK science base. This is also aided by the transfer of knowledge and skills between academia and industry. The PDRA and Technician will both receive full and relevant training. Several former PhD students are now working within the biotechnology or biomedical sector.

Publications

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Passmore JB (2020) Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation. in Biochimica et biophysica acta. Molecular cell research

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Schrader M (2019) Peroxisomes - cellular team players in SciTech Europa Quarterly

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Schrader M (2020) Organelle interplay-peroxisome interactions in health and disease. in Journal of inherited metabolic disease

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Schrader M (2020) Organelle interplay-peroxisome interactions in health and disease. in Journal of inherited metabolic disease

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Schrader M (2019) Zellweger UK - a glimmer of hope in SciTech Europa Quarterly

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Silva B (2020) Maintaining social contacts: The physiological relevance of organelle interactions in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Taatjes DJ (2019) Histochemistry and Cell Biology: 61 years and not tired at all. in Histochemistry and cell biology

 
Description We are address fundamental open questions related to the molecular mechanisms and pathways that mediate and regulate organelle dynamics and abundance. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions. Peroxisomes have vital, protective roles in lipid metabolism, signalling, and the combat of oxidative stress, thus influencing developmental and ageing processes. We are applying novel tools and cellular models to assess and modulate organelle dynamics and abundance, which may improve cell performance in health and disease.

We have so far produced a co-regulation map of the human proteome, which was able to capture relationships between proteins that do not physically interact or co-localize. This will enable the prediction and assignment of functions to uncharacterised human proteins. The co-regulation map can be explored at www.proteomeHD.net.

Exploring the map revealed unexpected co-regulation partners, namely the peroxisomal membrane protein PEX11ß with mitochondrial respiration factors.
This led to the identification of a novel interaction between two crucial cellular organelles in human cells - mitochondria and peroxisomes.

Peroxisomes and mitochondria in mammals are intimately linked and cooperate in the breakdown of fatty acids and cellular energy balance. Using live cell imaging we revealed that PEX11ß mediates the formation of membrane protrusions, which emanate from peroxisomes and interact with mitochondria. They likely function in the metabolic cooperation and crosstalk between both organelles, and may facilitate transfer of metabolites during mitochondrial energy (ATP) production.
Exploitation Route The project has high potential to contribute to therapeutic approaches, not only for the treatment of organelle-based disorders but also for pathological conditions associated with oxidative stress, cellular energy regulation and cellular ageing.
Sectors Communities and Social Services/Policy,Education,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.exeter.ac.uk/news/research/title_763295_en.html
 
Description Our findings have so far contributed to a better understanding of peroxisome-mitochondria interplay and co-regulation of human proteins which is medically relevant. Our findings have been used by other scientists to identify new proteins within the human proteome, which are co-regulated. This resulted in the association of new functions with human proteins and greatly supported our concept of the peroxisome-mitochondria connection which is of biological and medical importance. Our findings allow the identification of new relationships between human proteins and thus, the identification of new protein functions. Our findings have led to the development of tools to identify co-regulation of human proteins (co-regulation map). Our findings have supported diagnostics of peroxisome-organelle based disorders (e.g. peroxisome-mitochondria).
First Year Of Impact 2018
Sector Education,Healthcare
Impact Types Cultural,Societal

 
Title Reporter cell line 
Description We created a dual reporter cell line for luminescence -based reporter assays to identify components which will modulate peroxisome abundance in human cells. 
Type Of Material Cell line 
Year Produced 2014 
Provided To Others? No  
Impact The reporter cell line will be used in cooperation with our industry partner to perform a large scale compound screen to identify novel compound to modulate organelle/peroxisome abundance. This will be beneficial for the development of therapies to treat organelle/peroxisome-based disorders (including age-related disorders, neurodegeneration). 
 
Title Co-regulation map of the human proteome 
Description We supported our cooperation partner in generating/validating a machine learning algorithm to reveal functional associations between co-regulated human proteins. 
Type Of Material Computer model/algorithm 
Year Produced 2019 
Provided To Others? Yes  
Impact The new co-regulation map identifies new relationships between human proteins, and thereby enables functional annotation of human proteins. Co-regulation was able to capture relationships between proteins that do not physically interact or colocalize. Based on co-regulation data, we discovered a new mechanism of organelle interaction/interface between peroxisomes and mitochondria in human cells mediated by PEX11ß with mitochondrial respiration factors. 
URL http://www.proteomeHD.net
 
Description Co-regulation map 
Organisation Technical University Berlin
Country Germany 
Sector Academic/University 
PI Contribution We provided experimental evidence/proof-of-principle for a new machine learning algorithm to reveal-regulated proteins in the human proteome.
Collaborator Contribution The partner shared unpublished information and research data and provided access to a novel prediction tool (co-regulation map). Furthermore, protein/organelle samples were analysed by the partner.
Impact The cooperation resulted in a cooperative high-impact publication in Nature Biotechnology and in a new tool/algorithm, a co-regulation map for human proteins, which is publicly available.
Start Year 2018
 
Description Press release - protein co-regulation map 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release to inform and increase awareness of new discoveries and tool in cell biology/bioinformatics with link to biomedicine/human disease with respect to co-regulation of human proteins and identification of protein functions. It sparked questions and discussions, increased awareness and interest.
Year(s) Of Engagement Activity 2019
URL http://www.exeter.ac.uk/research/newsandevents/news/title_763295_en.html
 
Description Widening paricipation -work experience placement 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Work experience placement week for yr 10 students from a local school; the pupils spend a week in the research team performing experiments related to molecular cell biology, organelle biology/peroxisomes, analysed data, discussed results and obtained insight into the day-to-day work of scientists, academics, experimental officers and students. Several research facilities in the Dept. were visited and the students took part in demonstrations. Overall, this generated increased interest in and understanding of Biosciences and science in general, sparked questions and discussions and supported decision-making for future careers.
Year(s) Of Engagement Activity 2019
 
Description ZUK charity session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A member of the Zellweger UK charity and parent/carer of a Zellweger patient informed UG/PG students and academic staff about the work and aims of the ZUK charity and the day-to-day life with a Zellweger patient. This patient-centred session complemented learning activities on the underlying biological science and diagnostics. The session was very well received and sparked questions and discussions afterwards. It greatly increased awareness of peroxisome-based disorders and our BBSRC funded research.
Year(s) Of Engagement Activity 2019
URL http://www.zellweger.org.uk
 
Description Zellweger UK Charity Family Conference 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Family Meeting/Conference with patients and carers dealing with peroxisome biogenesis disorders/Zellweger Syndrome Disorders as well as researchers and national/international medical experts (USA, The Netherlands). Presentation about peroxisome biology, role in health and disease and peroxisome/organelle research in the UK sparked questions and discussions afterwards, and plans to increase awareness of PBDs (in the UK and internationally) were further developed.
Year(s) Of Engagement Activity 2019
URL http://www.zellweger.org.uk/