Mitophagy Signalling in Health and Disease

Lead Research Organisation: University of Dundee

Abstract

The cells of our body are constantly exposed to potentially damaging agents from both external sources, such as the sun's harmful UV rays or pathogenic bacteria, as well as internal sources, including free radicals produced by the cell’s metabolic pathways. A key mechanism that helps us cope with this onslaught is autophagy (which literally means self-eating) whereby damaged and unwanted cellular components, such as mitochondria, are targeted for degradation and recycling. Recent work has indicated that impaired autophagy is linked to many diseases such as cancer and neurodegenerative conditions such as Parkinson’s, therefore any drug that could target this process might be advantageous in treating these diseases. The actual mechanisms of autophagy remain elusive and the aim of my lab is to understand how autophagy is regulated and proceeds at the molecular level. We also aim to unravel how the disruption of autophagic pathways can lead to disease and to exploit this information to develop novel therapeutic strategies.

Technical Summary

A major focus of this research is to decipher the signals that regulate autophagy under physiological conditions and we are particularly interested in the autophagy of mitochondria, a process termed mitophagy. Mitochondria, the key energy-generating organelles of the cell, have the potential to cause great cellular harm and death when they become damaged, in part due to uncontrolled release of cytochrome c and production of reactive oxygen species. Because of this, a failure in mitochondrial quality control has strong links to diseases such as cancer and neurodegeneration. One critical quality control pathway that is emerging is mitophagy, the clearance of mitochondria by autophagy. Autophagy is a catabolic process whereby a membrane compartment, termed an autophagosome, engulfs excess, impaired and/or toxic components and delivers them to the lysosome for degradation. It is now evident from cell-based work that mitochondria can be specifically incorporated into autophagosomes, but how and where this occurs physiologically is still poorly defined. Addressing these issues is vital, not only for understanding the aetiology of diseases such as Parkinson’s, but also because mitophagy has great potential as a therapeutic tool. Our work has revealed for the first time that mitophagy occurs at a high rate in specific cells and tissues in vivo under normal conditions, including those of clinical relevance such as dopaminergic neurons in relation to Parkinson’s. However, we do not know the signalling pathways controlling these instances of mitophagy. Our objective is to resolve the mechanisms that regulate physiological mitophagy, delineate the relevant signalling pathways and to determine how these mechanisms relate to development of disease. Using a combination of biochemistry and cell biological techniques, we will molecularly define how the autophagy initiating ULK1 kinase complex becomes activated to drive mitophagy and in turn determine when and where this becomes important in vivo.

Publications

10 25 50
 
Description Priority Target Award Program
Amount $285,929 (USD)
Funding ID 11470.01 
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2017 
End 11/2020
 
Description Andrew P 
Organisation The Garvan Institute for Medical Research
Department Diabetes and Metabolism
Country Australia 
Sector Hospitals 
PI Contribution We are supplying reagents and expertise.
Collaborator Contribution We will gain information of the role of exercise and muscle mitophagy
Impact .
Start Year 2016
 
Description DSTT renewal 2016 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation Merck
Department Merck Serono
Country Germany 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description Exploring mitophagy in the retina 
Organisation Centre for Biological Research (CIB)
Country Spain 
Sector Public 
PI Contribution We have provided reagents and expertise
Collaborator Contribution They have provided reagents and expertise
Impact One publication: 1: McWilliams TG, Prescott AR, Villarejo-Zori B, Ball G, Boya P, Ganley IG. A comparative map of macroautophagy and mitophagy in the vertebrate eye. Autophagy. 2019 Feb 20:1-13. PubMed PMID: 30786807.
Start Year 2018
 
Description Jo P 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We are supplying reagents and expertise.
Collaborator Contribution We will gain knowledge on the potential of mitophagy for disease treatment.
Impact .
Start Year 2016
 
Description Steve J 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are undertaking experimental work and contributing expertise and intellectual input.
Collaborator Contribution Collaborators are undertaking experimental work and contributing expertise and intellectual input..
Impact .
Start Year 2016
 
Description MRC Festical of Medical Research Inside Out Science Open Day 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Festival of Medical Research Inside Out Science Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students (from the Schools of Life Sciences and Medicine at the University of Dundee). The MRC Festival aimed to inform, inspire and stimulate thinking about medical research. Our event was held within the School of Life Sciences and involved seven table top engagement activities, five ten-minute accessible science talks given by PhD students and early career researchers, three lab tours and three videos about the scientific work of the Unit on loop with visitors. There were two new activities called Chromatography and Stem Cell Game trialled that were developed by MRC PPU staff and students plus previously developed activities. Prior to the open day event, a primary six class at Glebelands Primary School attended a 90 minute session to give valuable feedback on talks and new activities.

Members from my lab who participated were;
Lea Wilhelm - Post Doctoral Researcher
Maria Zachari - PhD Student
Francois Singh - Post Doctoral Researcher

Overall, 129 members of public (generally family groups) were reached with 103 people visiting on the day, a further 24 Primary Six pupils and their two teachers who gave feedback on the new talks and activities ahead of the event.
The event met a number of the objectives and key messages from the 2018 - 2023 MRC Protein phosphorylation and ubiquitination Public Engagement and Communications Plan which were:

Communications Objectives
1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible.
2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease.

Key Messages
1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease.
2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research.
3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it.

Feedback
The visitors to the event were a mixture of ages which included family groups (children under 16 years) and adults up to 70 years of age. Feedback indicated that they enjoyed themselves overall and said they would come to a similar event again. Highlights included a game developed on the topic of Stem Cells and the laboratory tours. Around a third of visitors polled had not attended a University of Dundee event before indicating we were reaching new audiences.
The talks in particular stimulated a number of questions from the audience such as:
• How long does it take for a cell to divide?
• What would happen if you lost all your amino acids?
• Is it only older people who get Parkinson's?
• What is it about not being obese that helps protect you from Alzheimer's?
• What does wildtype mean?

Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too.
Year(s) Of Engagement Activity 2018
 
Description MRC Festival of Medical Research Open day 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 MRC Festival of Medical Research Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students. The event was held within the School of Life Sciences and involved table top activities, two ten-minute-talks, and a careers session with secondary school pupils from the MRCPPU partner school, Baldragon Academy.
My research was represented in this program of work by lab members working with students to demonstrate DNA extraction from fruit.

Overall, 40 S1 and S2 school pupils from Baldragon Academy visited on the day accompanied by their two teachers.
The event met a number of the objectives and key messages from the 2018 - 2023 MRC PPU Public Engagement and Communications Plan:

PPU Communications Objectives
1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible.
2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease.

Key Messages
1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease.
2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research.
3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it.

Feedback
Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too. They said that they enjoyed taking part in the activities and sharing their research with others.
Examples of comments about what they most enjoyed were:
• I like that most kids were enthusiastic and wanted to try doing experiments
• Good experience talking to an age group I wouldn't normally engage with
• The variety of questions
Examples of comments about what they least enjoyed were:
• Some kids difficult to engage
• Not enough time per group
• Rushed switch-overs
The pupils asked a lot of questions indicating that they were following and understanding the various activities. They covered the process of scientific research, the impacts on people from the diseases that are studied by MRCPPU researchers and about life as a scientist.
Year(s) Of Engagement Activity 2019
 
Description Parkinson's Dundee Research Interest Group 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact The MRC PPU opened its doors for a visit for people affected by Parkinson's, organised by the Dundee Research Interest Group (DRIG). Over 25 people spent the afternoon not only talking to MRC PPU Director Professor Dario Alessi and the many researchers working to unravel the mechanisms that cause Parkinson's, but also going on a tour of the Centre for Translational and Interdisciplinary Research (CTIR) Mass Spectrometry facility, an immunofluorescent microscopy demonstration, and having other scientists explain their work at the bench. My lab were directly involved in demonstrating how microscopy is used to visualise intracellular processes related to Parkinson's.

The feedback from everybody involved has been overwhelmingly positive.
Year(s) Of Engagement Activity 2019
URL https://www.ppu.mrc.ac.uk/news/meet-scientists-laboratory-tour
 
Description Scientific Lead on Animating Science 
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 Animating Science is an exciting pilot project under the banner of STEAM (taking STEM and adding A for arts). University of Dundee's School of Life Sciences has partnered with Dundee Contemporary Arts Learning to deliver a unique art and science collaborative programme supported by Wellcome through the Institutional Strategic Support Fund.
Animating Science aims to develop stop motion animation skills with pupils and teachers (P7 - S3) and support them in creating animated films about Life Science concepts and processes. This will deepen pupils' engagement and science understanding and make science learning more fun.
Researchers contributed guidance on a science topic chosen by participating classes, including a lesson with hands-on activities and experiments. They then re-visited the class during the writing and filming of the project to advise on the story and script to ensure it was scientifically accurate. At the end of the project they attended a 'film premiere' where the finished product was shown to the entire school as well as parents and teachers.
Significant impact (drop down box)
• Audience reported change in views, opinions or behaviour
• Own/colleagues reported change in views or opinions
• Decision made or influences
Pupils taking part reported increased confidence engaging in science as well as increased fluency in scientific vocabulary. Teacher observation reported excellent levels of team working and engagement from pupils who are traditionally more disruptive or unengaged with regular classwork.
"[I learned] to co-operate, pay attention, animate and play with it. It helped me be creative."
As a result of taking part in this project the concept of using animation to cement science learning has been adapted as part of an undergraduate module.
Year(s) Of Engagement Activity 2016,2017,2018,2019,2020
URL http://www.lifesci.dundee.ac.uk/impact/schools-outreach/animating-science-workshops
 
Description Work Experience Week 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The public engagement aims of the School of Life Sciences are to:
1. Build on our creative partnerships to deliver a high quality, innovative engagement programme.
2. Engage a range of people with our research.
3. Collaborate with our local communities to meet their needs and widen our reach.
4. Promote and support a culture of active participation in public engagement within our life sciences community. This includes students, research and non-research staff.
We have identified with local schools that access to laboratory experience and scientific workshops is a gap in the current provision by schools that could help to encouraging pupils to consider science as a future career. The "Work Experience week" is a programme with the objective of engaging pupils in scientific research and transferable skills. Priority is given for students from schools in areas of low income. It ran from July 30-August 3, 2018 for 24 S6 pupils from a variety of local secondary schools. As part of this week they took part in a variety of activities facilitated by the School of Life Sciences including a careers speeding dating session, tours of various scientific facilities, visits to the James Hutton Institute and the School of Medicine, ethics discussions, group presentations and four separate sessions of lab-based practical work.

My lab hosted a small group of pupils for a 3-hour lab session, giving them hands-on experience in a working lab and answering questions about careers and study.

Evaluation was undertaken to assess the quality of the Work Experience Week for pupils. Feedback was overwhelmingly positive, including one student who said: "The work experience week at the SLS gave me a real insight into the different aspects of studying a course at Life Sciences from drug discovery to plant sciences. The week has really made me consider choosing Dundee University as a place to study as all the staff and students were so welcoming and the different range of facilities was amazing. The experience has also made me less nervous and more excited about applying to a science degree at university if my first choice doesn't work out. I gained a lot of useful information that will benefit me in real life and in applying to university in the near future."
Year(s) Of Engagement Activity 2018
 
Description Work Experience Week 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 The Work Experience Week ran from July 29-August 2, 2019 for 21 S6 pupils from a variety of local secondary schools. As part of this week they took part in a careers speeding dating session, tours of various facilities, visits to the James Hutton Institute and the School of Medicine, ethics discussions, group presentations and four separate sessions of lab-based practical work.
• I took part in the careers speed dating session, sharing my personal journey through study and work and answering questions.

Feedback was overwhelmingly positive, including one student who said: "I have learned that science is both independent and requires a team spirit because there is the aspect of freedom working on a topic of interest but also that scientists help each-other and collaborate."
Year(s) Of Engagement Activity 2019