Mitochondrial transport proteins in human physiology and disease

Lead Research Organisation: University of Cambridge

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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Boczonadi V (2018) Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease. in Genetics in medicine : official journal of the American College of Medical Genetics

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Duncan AL (2018) Cardiolipin dynamics and binding to conserved residues in the mitochondrial ADP/ATP carrier. in Biochimica et biophysica acta. Biomembranes

 
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 Role of mitochondrial carriers in circadian rhythm 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We are studying the role of mitochondrial carriers in circadian rhythm to understand changes in human physiology.
Collaborator Contribution Initiated the research,
Impact NA
Start Year 2015
 
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 Bassingbourn VC 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact During a question and answer session, Year 7 students (11-12 years) guess the MBU members' occupations. Impact: raised awareness.
Year(s) Of Engagement Activity 2019
 
Description Beccles Free School, Beccles 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my research group gave two outreach/widening participation talks at Beccles Free School, Beccles with the school liaisons officer at St. Catharine's College (one to year 8+9, the other to year 10+11): about 200 students in total.
Impact: increased awareness.
Year(s) Of Engagement Activity 2019
 
Description Benjamin Britten High School, Lowestoft 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my group gave an outreach/widening participation talk at Benjamin Britten High School, Lowestoft with the school liaisons officer at St. Catharine's College, Cambridge.
Impact: increased awareness.
Year(s) Of Engagement Activity 2019
 
Description Big Bang Eastern 
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 Member of my group participated in the Big Bang Eastern event, aimed at secondary school students aged between 11-18 years.
Impact: increased awareness; decisions made or influenced; plans made for future related activity (visit to the MBU by schools).
Year(s) Of Engagement Activity 2019
 
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 Big Biology Day 
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 Members of my research group participated in the Big Biology Day. They MBU took Mito-gami, "Destroying Mutant Mitochondrial DNA", DNA sequencing puzzles and colouring/activity books. There was much conversation about the science and career options.
Impact: increased awareness; requests for further information.
Year(s) Of Engagement Activity 2019
 
Description CRC Freshers' Fair 
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 Cambridge Regional College at Cambridge. Event themed at encouraging CRC students and apprentices to use their time constructively and inspire them to consider their future options and goals. Attended by a member of my research group. Feedback: increased awareness. A very successful event. We had a lot of interest from students studying science and we were asked to postpone our departure so that a particular group of students could visit us.
Year(s) Of Engagement Activity 2018
 
Description Chesterton Community College: Careers Carousel 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Members of the MBU showcased the Unit's science to Year 10 students (14-16 years), to give them a greater insight into some of the career options available to them so that they are better informed to make career choices and motivated to succeed in the coming months.
Impact: raised awareness; decisions influenced.
Year(s) Of Engagement Activity 2019
 
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 East Point Academy, Lowestoft 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my research group gave an outreach/widening participation talk at East Point Academy, Lowestoft with the school liaisons officer at St. Catharine's College, Cambridge.
Impact: increased awareness.
Year(s) Of Engagement Activity 2019
 
Description Life at University (St Catharine's College) 
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 20 gifted and talented students visited Cambridge from Lowestoft Sixth Form College for advice on university and Cambridge. This included an example lecture, and a university applications workshop.
Year(s) Of Engagement Activity 2019
 
Description Lowestoft Sixth Form College, Lowestoft (multiple events during the year) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my research group gave an outreach/widening participation talk at Lowestoft Sixth Form College, Lowestoft with the school liaisons officer at St. Catharine's College, Cambridge.
Impact: increased awareness.
Year(s) Of Engagement Activity 2019
 
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 Nuffield Placement Programme 
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 Work experience programme sponsored by Nuffield. One year 12 student spent 19 working days in the Unit, one of which was hosted by members of my research group.
Year(s) Of Engagement Activity 2018
 
Description Online promotion of the MRC MBU 
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 My research, and that of the MBU, is promoted in various ways online - via the Unit's website and on social media accounts such as facebook, Twitter, etc. Impact: dialogue, requests for further information, influence, potential collaborations and the recruitment of researchers, including early career researchers, to the Unit.
Year(s) Of Engagement Activity 2019
 
Description Open Day, Trinity Hall 
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 Open Day at Trinity Hall - aimed at encouraging students to apply to Cambridge for undergraduate study.
Year(s) Of Engagement Activity 2019
 
Description Ormiston Denes High School, Lowestoft 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my research group gave an outreach/widening participation talk at Ormiston Denes High School, Lowestoft with the school liaisons officer at St. Catharine's College, Cambridge.
Outcome: increased awareness.
Year(s) Of Engagement Activity 2019
 
Description Sir John Leman High School, Beccles 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my group gave two outreach/widening participation talks at Sir John Leman High School, Beccles with the school liaisons officer at St. Catharine's College, Cambridge.
Impact: increased awareness
Year(s) Of Engagement Activity 2019
 
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 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 2015,2017,2018,2019
URL http://www.sciencefestival.cam.ac.uk/about/past-festivals/2015-cambridge-science-festival
 
Description Visit by Longsands Academy, St Neots 
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 Membersof my research group participated in this event.
Visit to the MRC MBU by 21 students in Year 13 (16-18 years of age). "Biology Masterclass", followed by tour of unit (fly lab) and "meet the scientists" session. The students went on to visit CIMR during the afternoon. Collaboratively organised event.
Feedback:
Thank you so much to yourself and your colleagues for organising today's activities.
We all found it hugely helpful and interesting - providing the students with a very inspiring view into the world of scientific research and university life.
The day was so well organised- I must apologise for the disrupted start to the day with the late arrivals.
I really appreciated the thought that had gone into linking the theory seamlessly with our A level syllabus and allowing the students access to equipment that we only read about in our textbooks.
Once again thank you - please pass on our thanks to all your colleagues.
Year(s) Of Engagement Activity 2019
 
Description Visit to the MRC MBU by students of Hautlieu and Beaulieu Schools, Jersey 
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 Members of my research group participated in a Visit to the MRC MBU by 10 students ranging between 14-17 years of age. "Biology Masterclass", followed by tour of unit (fly lab) and an explanation of ATP synthase (with the Lego model) from John Walker. Finished with "meet the scientists" session and games.
The students were accompanied by four tutors.
Year(s) Of Engagement Activity 2019
 
Description What's My Line? Saffron Walden County High 
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 During a question and answer session, students guess the MBU members' occupations. 30 students; 5 x 15 minute sessions.
Impact: increased awareness.
Year(s) Of Engagement Activity 2019
 
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