Mitochondrial transport proteins in human physiology and disease

Lead Research Organisation: Medical Research Council

Abstract

The mitochondrion, nick-named the 'power house of the cell', is a special compartment of the human cell where components of sugar and fat are broken down to generate energy in the form of ATP. ATP is the chemical fuel used by the rest of the cell to carry out its activities, for example the contraction of muscle cells during movement. Two membranes, consisting of lipid, enclose the mitochondrion; the outer membrane is permeable for most compounds, but the inner membrane is tightly sealed. Mitochondrial transport proteins bind a compound on one side of the membrane and then carry it through the membrane to release it on the other side. Humans have more than 60 different transport proteins, carrying out a variety of known and unknown transport steps. We are interested in studying these transport proteins to identify the role of each of these carriers in cellular metabolism. Serious diseases have been associated with dysfunctional mitochondrial transport proteins and research is aimed at understanding in detail how they function to identify the cause of these diseases and to find possible cures.

Technical Summary

Mitochondria play a central role in the utilisation of sugars, amino acids and fat by the human cell. Pathways, such as the citric acid cycle, aspartate-malate shuttle and fatty acid oxidation are used to drive the synthesis of ATP via oxidative phosphorylation. Mitochondria also carry out the synthesis and degradation of amino acids (urea cycle) and the synthesis of haem and iron-sulphur clusters. Mitochondria are able to replicate, transcribe and translate mitochondrial DNA. They are also involved in the generation of heat during thermoregulation by dissipation of the proton gradient through uncoupling proteins. Since the mitochondrial inner membrane is impermeable to small polar molecules, a large number of transport proteins are involved in their import and export. The mitochondrial carrier family is one of the major transport protein families and there are 53 different members in man, but only half of their functions are known. There are also other transporters active in mitochondria, such as the mitochondrial pyruvate carrier and ABC transporters, but there could be many others, as a large number of compounds need to traverse the membrane. We are interested in studying mitochondrial transport proteins not only because of their central role in metabolism and physiology, but also because of their involvement in metabolic and neuromuscular disorders, obesity and fever, making them potential targets for drug development.
One area of our research is aimed at the identification of the remaining mitochondrial transporters to complete our understanding of their role in physiology and disease. Among the transported compounds are many key components of cellular metabolism, such as essential amino acids, co-factors, inorganic ions, nucleotides, and antioxidants.
Another area of interest is the discovery of transport proteins that are involved in human disease. Many mutations of mitochondrial transport proteins lead to metabolic, neurological and muscular mitochondrial diseases and it is likely that more links will be discovered through exome sequencing. We would like to understand the transport process at the atomic level to explain why these diseases occur.

Publications

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Bamber L (2007) The yeast mitochondrial ADP/ATP carrier functions as a monomer in mitochondrial membranes. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Investigating the functions of the remnant mitochondria of parasitic protozoa
Amount £98,288 (GBP)
Funding ID 089803/Z/09/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 12/2015
 
Title Bubble excluder 
Description Bubble exclusion in aerated fermentations 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact This methodology allows the on-line measurement of microbial cultures in fully aerated bioreectors. A patent has been obtained and we are in the process of making this technology available commercially. 
 
Title Location of the substrate binding site by symmetry analysis 
Description Detection of the substrate binding site in proteins with pseudo-symmetry 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact No subsequent impact 
 
Title Size determination of detergent micelles 
Description Determination of the size of membrane protein in detergents 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact This new approach allows the sizes of membrane proteins to be determined more ccurately and could be a new standard for the application of size exclusion chromatography 
 
Description Defective transport in motor neuropathy 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Chacterisation of the defective transporter
Collaborator Contribution Medical links to motor neuropathy
Impact paper in progress
Start Year 2014
 
Description Generation of conformation-specific nanobodies 
Organisation Free University of Brussels
Country Belgium 
Sector Academic/University 
PI Contribution Purified carriers inhibited in specified states
Collaborator Contribution selection of nano bodies
Impact nanobodies
Start Year 2014
 
Description Identification of mitochondrial carriers 
Organisation University of Bari
Country Italy 
Sector Academic/University 
PI Contribution Expression strains and transport technology
Collaborator Contribution genetics
Impact not yet
Start Year 2014
 
Description Identification of mitochondrial transport proteins 
Organisation University of Florida
Country United States 
Sector Academic/University 
PI Contribution Expression and characterisation of transport proteins
Collaborator Contribution bioinformatics
Impact not yet
 
Description Mitochondrial pyruvate carrier 
Organisation University of Geneva
Country Switzerland 
Sector Academic/University 
PI Contribution Bioinformatic and functional characterisation of the mitochondrial pyruvate carrier
Collaborator Contribution The discovery and characterisartion of the mitochondrial pyruvate carrier
Impact paper in science
Start Year 2012
 
Description Transport in the CoA synthesis pathway 
Organisation Carlo Besta Neurological Institute
Country Italy 
Sector Public 
PI Contribution Expression of transport proteins involved in the CoA pathway
Collaborator Contribution Discovery of key enzymes in the pathway
Impact not yet
Start Year 2014
 
Title Device for exclusion of air bubbles 
Description The invention shields measuring devices, such as optical probes, from the interference of air bubbles 
IP Reference WO2007096626 
Protection Patent granted
Year Protection Granted 2007
Licensed Commercial In Confidence
Impact in the process of obtaining commercial partners for the exploitation of this patent.
 
Title Bubble excluder and optical density measurements 
Description The spin-off company Cytoprom has brought the invention to the international markets 
Type Support Tool - For Fundamental Research
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact The product is involved in the monitoring of fermentation, which may aid the yield and quality of the fermentation products. 
URL http://cytoprom.com/
 
Company Name Cytoprom 
Description The aim is to sell the bubble excluder as part of a system to monitor cell density in fully aerated fermenters. 
Year Established 2011 
Impact Not yet, as we are in the starting phase.
Website http://cytoprom.com/
 
Description "Opportunites Ahead" (Guildhall) 
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 2017
URL http://www.mrc-mbu.cam.ac.uk/news/2768/opportunities-ahead-careers-fair-cambridge
 
Description Amgen Scholarship Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Symposium for undergraduates who have undertaken Amgen summer studentships in Cambridge. Edmund Kunji acted as a round table discussion leader, focused on what it is to pursue a scientific career.
Year(s) Of Engagement Activity 2017
URL https://amgenscholars.bio.cam.ac.uk/Cambridgeprogramme
 
Description Annual Unit Open Day 
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 60 members of the public (including sixth form students) visited the Unit to hear about our current research projects.

Enhanced interest in our activities. Request for participation in the Society of Biology's Big Biology Day (October).
Year(s) Of Engagement Activity 2014
 
Description Big Bang Fair London (Newham) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Demonstration of genetic influence on body characteristics in Drosophila, "Find My Mutant Fly" game, posters explaining the science, movies. Impact: increased awareness.
Year(s) Of Engagement Activity 2017,2018
URL http://nearme.thebigbangfair.co.uk/london/
 
Description Big Biology Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Showcase of MBU's work. Visitors grew crystals of protein and looked at and analysed their structures using the latest computer programs. Impact: Increased awareness, interest in joining the Unit.

Feedback: "MBU's activity is the best I have seen today"
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL http://www.hillsroad.ac.uk/college-life/news/2015/10/15/big-biology-day-at-hills-road-sixth-form-col...
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Hundreds of children and their parents came to our exhibit and participated in our activities.

There was a lot of positive response from the public and the exhibit featured in news bulletins.
Year(s) Of Engagement Activity 2010,2011,2012,2014,2015
 
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 via the Alpha Galileo website, Facebook and Twitter.

http://www.alphagalileo.org/
https://www.facebook.com/mrc.mbu/
https://www.facebook.com/mrc-mbu
Twitter - @MRC_MBU
http://www.mrc-mbu.cam.ac.uk/people/edmund-kunji
http://www.mrc-mbu.cam.ac.uk
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL http://www.alphagalileo.org/
 
Description Kimbolton School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Martin King: talk to students about scientific career.

Feedback: "I just wanted to drop you a line to thank you once again for giving up your Friday evening (again) to join me at the Kimbolton School Careers Evening last Friday. The organisers felt that the event had been a huge success and I know that Mr Skinner has received some very positive feedback from the students who attended. There really is no substitution for being able to ask questions about life as a scientist directly to a scientist - and it was good that Lizzie was there too this year to help to spread the load! I also very much appreciate your enthusiasm and willingness to offer up your time because Friday evening at such a distance is not an easy call!
Again, thanks so much for your continued commitment to the MRC's public engagement mission.Have a great weekend. Best wishes."
Year(s) Of Engagement Activity 2015
 
Description MEET (Mitochondrial European Educational Training) Symposium 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact From bench to bedside, and back: Patients MEET Researchers - providing an opportunity for patients and scientists to meet and discuss mitochondrial diseases.
Year(s) Of Engagement Activity 2016
URL http://www.itn-meet.org/MEET-Symposium-2016
 
Description MRC Centenary Open day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Presented talks on energy in biological systems

More open days for schools will be organised
Year(s) Of Engagement Activity 2013
URL http://www.mrc-mbu.cam.ac.uk/news-and-events/science-and-society
 
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.
Year(s) Of Engagement Activity 2015,2016
 
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 Open Day: Trinity Hall (two events in 2015) 
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 Schools
Results and Impact Open day for secondary school students and teachers. No specific feedback, but Edmund Kunji is always invited to attend these events.
Year(s) Of Engagement Activity 2015
 
Description Oxford Botanic Garden 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Fox Got You is a photographic installation celebrating six common plants which are at the origin of five major medicinal drugs. http://www.botanic-garden.ox.ac.uk/fox-got-you

Scientists at the MBU have been collaborating with the photographic artist, Francoise Sergy, whose exhibition is being shown during July and August at the Oxford Botanic Garden.

At a public event on Saturday, 11 July, visitors met the artist and the scientists, clinicians and patients involved in the project, who talked about their work and experiences.

Edmund Kunji represented the MBU and explained the stories behind photographs taken in the Unit.
Year(s) Of Engagement Activity 2015
URL http://www.botanic-garden.ox.ac.uk/fox-got-you
 
Description School student (shadow) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact A school student shadowed a scientist for a day
Year(s) Of Engagement Activity 2015
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave short presentations to secondry school children about studying at Cambridge University and academic life

Children applied to Cambridge
Year(s) Of Engagement Activity 2006,2007,2009,2010,2013
 
Description Society of Biology 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 Demonstrations led to questions and discussions, requests for further information. Also, a student (Oxford applicant) spent a day in the Unit, shadowing a scientist.

Feedback: "I was much inspired by your presentation to me last Saturday. I am hoping to apply to study Biological Science at Oxford, and while I haven't yet decided which area I will specialise in, yours seems a highly interesting and important area of research. I would really like to learn more about it by becoming involved. Is there any way I can do this, for instance if it were possible to spend a few days with your group sometime next year? Thank you again for such a fascinatingly detailed account last weekend - it was the highlight of the day."
Year(s) Of Engagement Activity 2014
 
Description St Ivo School - 2nd Annual Science Poster Competition 
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 Students research a topic of interest and create a poster which they then discuss with a panel of judges from a range of scientific backgrounds. MBU judges - Martin King and Penny Peck. Martin King to give a presentation on life at the MBU/in science.
Year(s) Of Engagement Activity 2017
 
Description St Mary's Primary School, Hackney - 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 showcased the Unit's science using Lego models, games, and experiments using a) oxygen and leaves in glass beakers placed under a lamp b) flies in a water bath and/or under a microscope. MBU members stood at fixed stations (tables) for each session of the programme, which was organised as a carousel event, with children rotating around the room in accordance with the programme. Feedback: We wanted to write and thank you and the team from the MRC for the wonderful science workshops you provided the children with last week. The feedback has been fantastic, with the children clearly feeling inspired to learn more about science through their enjoyment of the experiments and activities you provided. One of our Year 3 girls reported back, in no uncertain terms, that she has decided she will be attending the University of Cambridge when she is older!
Year(s) Of Engagement Activity 2018
URL http://st-marys.hackney.sch.uk/2018/science-week-january-2018
 
Description St Mary's School 
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 Careers carousel for years 5 and 6 (aged 9 and 10 years) at St Mary's School. Explanation of science and types of jobs at MRC MBU.

Impact: increased awareness.
Year(s) Of Engagement Activity 2016,2017
URL http://www.mrc-mbu.cam.ac.uk/news/2765/careers-carousel-st-marys-school-cambridge
 
Description The Perse School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to sixth form students about life as a research scientist (Martin King)
Year(s) Of Engagement Activity 2017
 
Description Trinity Hall (Groningen) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Tour of Trinity Hall to prospective students from Groningen, NL. Hosted by Edmund Kunji, who gave a lecture on life at Cambridge.

On the 13th of June, 2016, students from the University of Groningen visited the University of Cambridge. We were welcomed by Edmund Kunji, from Trinity Hall College. We were guided around the college and visited the beautiful library. Many students were surprised about the way life is organized in these colleges, since it is a lot different from the way students in the Netherlands experience University life. The lecture given by Mr. Kunji was very interesting, and the matter discussed had a good connection to the knowledge of the students. Especially the students that presented on the topic were extremely enthusiastic. Students were fascinated by the topic and really enjoyed their visit to this University.
Many thanks to Mr. Kunji for his hospitality! We had a great time.
Year(s) Of Engagement Activity 2016
 
Description Trinity Hall Open Days 
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 Schools
Results and Impact Around 50 potential students attended my talk on studying at Cambridge and being a scientist

They asked for my participation in other events. Nice feedback.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
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. Feedback: "Thank you very much for these very informative slides. I don't have any questions on them as of now, but if I do have, I will revert to you, if I may. ?The whole CSF presence in the Clinical School was excellent, and the MRC's contribution was very much appreciated."

 Interest in attending the Unit's open day in June.
Year(s) Of Engagement Activity 2015,2017,2018
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 Schools
Results and Impact Participation in video filming for MBU website (Cambridge TV)
Year(s) Of Engagement Activity 2016,2017
 
Description Visitors from Kyushi University, Japan 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Short tour and overview of Mitogenetics Laboratory, fly lab, meet the scientists session.
Year(s) Of Engagement Activity 2016
 
Description Work Experience visit (MBU) 
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 3 Year 10 students visited the MBU for a week each during a work experience/shadowing project involving various research groups/environments, chaperoned throughout by individual members of the Unit. Presentation by the visitor at the end of their week(s).
Year(s) Of Engagement Activity 2016,2017