Mitochondrial oxidative damage and human diseases

Lead Research Organisation: Medical Research Council

Abstract

A number of human diseases are associated with increased cell death caused by free radicals. These include degenerative diseases such as Parkinson's disease, Friedreich's ataxia and diabetes. Free radicals are reactive by-products of normal metabolism that damage cell components thereby disrupting normal function and leading to cell death. Mitochondria are the major source of free radicals within cells. These free radicals are formed as mitochondria consume the oxygen we breathe to make energy available to the cell. Mitochondria are also central to determining how cells die, consequently free radical damage to mitochondria is an important cause of cell death. We have developed procedures to target novel molecules to mitochondria. The hope is that these new molecules will enable us to elucidate the mechanisms by which free radicals damage mitochondria and increase cell death in human diseases. Some of these molecules are antioxidants that should block the effects of free radicals. Therefore this approach may also lead to novel therapies to decrease mitochondrial oxidative stress in human diseases such as Alzheimer's Disease and Parkinson's Disease.

Technical Summary

Mitochondria are central to the function of human cells because they make energy available to the cell in a usable form and because they are central to a number of pathways of cell death. Consequently it is unsurprising that defects in mitochondrial function contribute to a number of human diseases, including neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia. Damage to mitochondria also contributes to the pathophysiology of heart attack, stroke and diabetes. In this project my group are developing new tools to target molecules to mitochondria in order to understand the processes by which mitochondrial damage occurs and to develop ways in which this damage can be prevented or repaired in human diseases.

In carrying out this work we seek to understand how mitochondrial damage occurs in yeast, cultured mammalian cells and in rodent models of mitochondrial damage. One of the most important causes of mitochondrial damage is thought to be the formation of free radicals by mitochondria as a byproduct of their normal function. These short lived but reactive species cause damage to mitochondria DNA, proteins and lipids thereby disrupting normal mitochondrial function. A consequence of this damage is that it causes cells to undergo cell death by both apoptotic and necrotic pathways. We are particularly interested in understanding the links between mitochondrial damage and increased cell death.

To unravel the role of mitochondrial free radicals in cell death requires a range of techniques from molecular biology, cell biology and biochemistry. In addition to these standard approaches, we are also developing a strategy that is proving to be particularly useful. This is the selective targeting of molecules to mitochondria within cells. To do this we use the large membrane potential across the mitochondrial inner member to drive the uptake of lipophilic cations to which we have attached biologically active molecules. These active molecules include antioxidants and reporter molecules designed to respond to free radicals. By using these molecules we are able to both estimate and block mitochondrial oxidative damage, and thereby infer its role in cell death. In related work we are also developing strategies to direct large molecules such as proteins and nucleic acids to mitochondria in order to repair the damage caused to mitochondria by free radicals.

The approaches we are developing may allow us to measure or manipulate mitochondria processes independently of the rest of the cell. This has scientific potential in helping us understand the roles of mitochondria within the cell. As some of the molecules being developed may prevent or repair mitochondrial damage they may lead to improved therapies for human diseases involving mitochondrial dysfunction. These include degenerative diseases such as Parkinson's disease and diabetes and the general pathological changes associated with ageing.

Publications

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Bhattacharjee A (2016) The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. in The Journal of biological chemistry

 
Description BBSRC Grant (with Dr Richard Hartley)
Amount £38,000 (GBP)
Funding ID BB/I012923/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2011 
End 07/2014
 
Title Uni-cam-med 
Description The mitochondria-targeted S-nitrosating agent MitoSNO is at the early stages of being developed as a potential drug for cardiac ischemia reperfusion injury. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact .. 
 
Description UCL 
Organisation University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on redox changes in fruitflies with age.
Collaborator Contribution ..
Impact ..
 
Description Uni-cam-med 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on role of mitochondria in ischaemia-reperfusion injury
Collaborator Contribution ..
Impact ..
Start Year 2007
 
Description Uni-cam-surgery 
Organisation University of Cambridge
Department Department of Surgery
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on use of mitochondria-targeted compounds on organ preservation.
Collaborator Contribution ..
Impact ..
Start Year 2009
 
Description Uni-cam-wbic 
Organisation University of Cambridge
Department Wolfson Brain Imaging Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on use of mitochondria-targeted PET probes.
Collaborator Contribution ..
Impact ..
Start Year 2007
 
Title Mitochondira targetedd NO donors 
Description Targeting NO donors to mitochondria 
IP Reference US20100240615 
Protection Patent application published
Year Protection Granted 2010
Licensed No
Impact None
 
Description Attendance at various conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Scientific discussion/collaboration.

..
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description Big Biology Day 
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 Members of the MRC MBU participated in the Big Biology Day 2017 at Hills Road Sixth Form College. Scientists explained the Unit's research with hands-on activities. These included experiments using Drosophila melanogaster - with fluorescent markings and temperature sensitivity, our "Find the mutant fly" game, colouring books and posters.
Year(s) Of Engagement Activity 2017
URL http://www.hillsroad.ac.uk/college-life/events/2017/10/14/default-calendar/big-biology-day
 
Description Broadening Horizons (Anglia Ruskin) 
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 Careers fair for primary school students.
Year(s) Of Engagement Activity 2016
URL http://www.mrc-mbu.cam.ac.uk/news/2678/broadening-horizons-careers-fair-primary-school-students
 
Description Dissemination of scientific achievements via the internet 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of scientific achievements to the general public, scientists and others via the Unit's website, Alpha Galileo, Twitter and Facebook.

https://www.facebook.com/mrc.mbu/
Twitter - @MRC_MBU
http://www.mrc-mbu.cam.ac.uk
http://www.alphagalileo.org
http://www.mrc-mbu.cam.ac.uk/people/mike-murphy
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL http://www.mrc-mbu.cam.ac.uk/people/mike-murphy
 
Description Goop Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article for Goop Newsletter, "Why Your Mitochondrial Health Matters".
Year(s) Of Engagement Activity 2018
URL https://goop.com/wellness/health/why-your-mitochondrial-health-matters/
 
Description MRC MBU Annual Open Day/MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Overview of work at the MRC MBU; explanations of how mitochondrial dysfunction causes mitochondrial diseases. Audience: Secondary school students, tutors, general public and scientists from neighbouring institutes. Impact: increased awareness. Impact: request to visit schools in Hertfordshire.
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.mrc-mbu.cam.ac.uk/news/2335/open-day-2015
 
Description Mayfield Primary School Science Day 
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 Members of the MBU visited Mayfield Primary School, Cambridge to participate in their Science Day. This was a classroom based event, with students in Reception (aged 4 and 5 years) rotating around the room. After a short talk, the children interacted with Lego models, pipetting and colouring.
Year(s) Of Engagement Activity 2017
 
Description Opportunites Ahead 
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 event is aimed at school students in years 5 & 6 in the morning followed by students from secondary schools, sixth-forms, recent school and college leavers and parents in the afternoon. The idea is to showcase the wide variety of companies in the Cambridge area and get young people excited about their future.

Signpost 2 Skills is a new service designed to guide students from education and into working life by bringing employers into schools and students into businesses. It is funded by the Greater Cambridge Greater Peterborough LEP and the Greater Cambridge City Deal, and delivered by social enterprise, Form the Future.
Year(s) Of Engagement Activity 2016
URL http://www.mrc-mbu.cam.ac.uk/news/2620/opportunities-ahead-careers-fair
 
Description Public Engagement Training 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact PE training; aims - to increase confidence in public engagement skills in MRC scientists, to raise awareness of local and national incentives for PE and science communication activities, to encourage MRC scientists to consider new audiences for their public engagement activities, to develop public engagement skills in MRC scientists ahead of the MRC Festival of Medical Research (June).
Year(s) Of Engagement Activity 2016
 
Description Queen Edith's Primary School 
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 Members of the MBU visited Queen Edith's Primary School, Cambridge to participate in their Science Day. This was a carousel-type event, with students in years 1-4 rotating around the room. The demonstrations included Lego models, computer games, pipetting and DNA sequencing puzzles. Feedback: Thank you so much for coming here today. The children have not stopped talking about it since leaving the room.
Year(s) Of Engagement Activity 2017
 
Description University of Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Demonstrating how mitochondrial dysfunction leads to illness and giving insight into the work of the MBU.

Interest in attending the Unit's open day in June; requests for summer studentships and work experience visits.
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.sciencefestival.cam.ac.uk/about/past-festivals/2015-cambridge-science-festival
 
Description Videos for website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Filming for "Students' Perspectives" video with work experience student
Year(s) Of Engagement Activity 2017
 
Description Women in Science at Comberton Village College 
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 aim of the event was to encourage female students to consider sciences/technology and engineering as a career option available to them. It is hoped that the students who attended the event will be better informed to make career choices and motivated succeed in the coming months. Our scientists took a presentation, along with Lego models and DNA sequencing puzzles, and the students were heavily engaged in dialogue during the event.
Year(s) Of Engagement Activity 2017
 
Description Work Experience 
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 Visit by three Year 10 students (age 15) to the Unit for a week each - work experience/shadowing in various research groups/environments, chaperoned throughout by individual members of the Unit. Presentation by the visitor at the end of their week.
Year(s) Of Engagement Activity 2016