Mitochondrial Complex I

Lead Research Organisation: Medical Research Council

Abstract

Complex I (NADH:ubiquinone oxidoreductase) catalyses the first step in the mitochondrial electron transport chain. Electrons from NADH are used to convert oxygen to water and the energy liberated is trapped in ATP and ultimately used as the body's energy source. They may also escape from complex I and go on to cause oxidative stress in the cell. Complex I is the largest and least well understood enzyme of the respiratory chain and there is no structural information pertaining to the mammalian enzyme. We aim to use structural, functional and spectroscopic techniques to gain a detailed and integrated picture of how complex I "couples" electron transfer to proton transfer, thus making the energy available for ATP generation, and to understood how electrons escape the tighly controlled system, resulting in the formation of reactive oxygen species. Subsequently, by combining these approaches with studies of complex I in the cell, we aim to gain a molecular-level understanding of medically-relevant complex I dysfunctions.

Technical Summary

Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and ß-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force that powers ATP synthesis. It is also a major contributor to cellular production of reactive oxygen species (ROS). Complex I is linked to medicine on many different levels: from mutations in its subunits and assembly factors that cause mitochondrial diseases, through the production of reactive oxygen species and oxidative damage (which may be relevant to neurodegenerative diseases such as Parkinson’s disease), to complex I as a potential drug target in diabetes, ischaemia-reperfusion and cancer, and complex I-linked drug side effects. Understanding the functions and dysfunctions of complex I in these contexts is an intellectual and scientific challenge for both medical and basic scientists that must be tackled on multiple levels. Basic molecular knowledge of the enzyme’s structure and mechanism is required to provide a foundation for biomedical function-dysfunction studies of complex I in mitochondrial and cellular systems of greater complexity. The central thrust of the future work of the Mitochondrial Complex I group is to develop and apply structural and mechanistic knowledge about complex I, in order to answer questions about its role in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions. Thus, we are working toward a high resolution structure of the enyzme, developing model systems for the study of mutations in order to determine the enzyme mechanism and define the molecular-level reasons for genetic complex I dysfunctions, and working with material from rodent model systems and cultured cells to study complex I-related pathologies directly in mammalian cells. On multiple levels these studies also allow complex I-drug interactions to be evaluated as pharmocological mechanisms and the causes of side effects.

Publications

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Agip AA (2019) Mammalian Respiratory Complex I Through the Lens of Cryo-EM. in Annual review of biophysics

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Armstrong FA (2011) Reversibility and efficiency in electrocatalytic energy conversion and lessons from enzymes. in Proceedings of the National Academy of Sciences of the United States of America

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Bassegoda A (2014) Reversible interconversion of CO2 and formate by a molybdenum-containing formate dehydrogenase. in Journal of the American Chemical Society

 
Description AOX collaboration 
Organisation University of Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of the alternative oxidase in a coupled system to study complex I
Collaborator Contribution Provision of the AOX over-expression system and expertise
Impact Angew Chem Int Ed Engl. 2016, 55, 728-31 A Self-Assembled Respiratory Chain that Catalyzes NADH Oxidation by Ubiquinone-10 Cycling between Complex I and the Alternative Oxidase. Jones AJY, Blaza JN, Bridges HR, May B, Moore AL, Hirst J.
Start Year 2014
 
Description Advanced EPR studies of complex I 
Organisation University of Oxford
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of knowledge/expertise
Collaborator Contribution Advanced EPR studies of complex I
Impact 21033838 Multidisciplinary - biochemistry and advanced spectroscopy.
Start Year 2008
 
Description EPR on complex I 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Preparation of enzymes and expertise on complex I
Collaborator Contribution EPR spectroscopy on complex I samples
Impact J Hirst and M. M. Roessler, Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I, Biochim. Biophys. Acta (in press) Mutlidisciplinary: biochemistry and spectroscopy
Start Year 2015
 
Description Electron microscopy 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Protein preparation, data analysis and interpretation, preparation of manuscript for publication
Collaborator Contribution Electron microscopy, data analysis and interpretation, preparation of manuscript for publication
Impact Publication of an article in Nature
Start Year 2013
 
Description Fourier transform IR studies of complex I 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of knowledge/expertise
Collaborator Contribution Fourier transform IR studies of complex I
Impact 16634627
 
Description Immunomet 
Organisation Immunomet Therapeutics
Country United States 
Sector Hospitals 
PI Contribution Experimental work aimed at structure of a biguanide bound complex I
Collaborator Contribution Funding and chemical compounds
Impact None yet
Start Year 2017
 
Description Inhibiting of complex I by biguanides 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution Research into actions of biguanides on complex I
Collaborator Contribution Expertise in application of biguanides for cancer treatment
Impact Two publications
Start Year 2012
 
Description Leeds cryoEM 
Organisation University of Leeds
Department School of Computing Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Enzyme preparation, biochemistry, cryoEM grid preparation, data analysis
Collaborator Contribution Microscopy data collection and analysis
Impact None yet
Start Year 2017
 
Description Mossbauer on complex I 
Organisation Max Planck Society
Department Max Planck Institute for Biophysical Chemistry Goettingen
Country Germany 
Sector Public 
PI Contribution Preparation of protein samples and interpretation of data
Collaborator Contribution Recording and interpretation of spectroscopic data
Impact Bridges, H. R., Bill, E. & Hirst, J. (2012). Mössbauer spectroscopy on respiratory complex I: the iron-sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized. Biochemistry 51, 149-158.
Start Year 2008
 
Description Photoaffinity labelling of complex I 
Organisation University of Kyoto
Department Division of Applied Life Sciences
Country Japan 
Sector Academic/University 
PI Contribution Expertise and materials
Collaborator Contribution New information about complex I
Impact Publication Murai et al. (2011)
Start Year 2010
 
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 the MRC MBU, with a guest from the MRC Cancer Unit, participated in the Big Biology Day 2016 at Hills Road Sixth Form College. Scientists explained the Unit's research with hands-on activities, such as crystallography, DNA sequencing puzzles and computer-based protein analysis.... and good use was made of the whiteboard!
Year(s) Of Engagement Activity 2016
URL http://www.mrc-mbu.cam.ac.uk/news/2650/big-biology-day-2016
 
Description Cambridge science festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Members of my group engaged with the public to better inform them about our interests and activities

Members of the public were better informed
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Careers Carousel - CAM-AST 
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 aims of the event were to give Year 11 students 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.
Year(s) Of Engagement Activity 2017
 
Description Careers Carousel - St Mary's School, Cambridge 
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 aims of the event was to give Year 5 and 6 students a greater insight into some of the career options available to them so that they are better informed in advance of making career choices.
Year(s) Of Engagement Activity 2017
 
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 Promotion of my research and scientific achievements via the Unit's website and social media.
Year(s) Of Engagement Activity 2015,2016
URL http://www.mrc-mbu.cam.ac.uk/people/judy-hirst
 
Description MBU Open Day 
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 Public/other audiences
Results and Impact Members of public learned about our activities and interests
Year(s) Of Engagement Activity 2014
 
Description MRC MBU Annual 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 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 2015,2017
URL http://www.mrc-mbu.cam.ac.uk/news/2335/open-day-2015
 
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 Redesign of Public Engagement Posters 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Daniel worked hard at redesigning the MBU's PE posters to incorporate our new University logo.
Year(s) Of Engagement Activity 2017
 
Description Talk at Boehringer-Ingleheim 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Discussion about possible research collaboration

Research Collaboration pending
Year(s) Of Engagement Activity 2006
 
Description Talking to A level students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Students interested in science and studying at good universities
Year(s) Of Engagement Activity 2011,2012,2013,2014
 
Description The Fox Got You 
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, including my research group, collaborated with the photographic artist, Francoise Sergy, whose exhibition was 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, which featured substantial contributions from me and the members of my research group.
Year(s) Of Engagement Activity 2015
URL http://www.botanic-garden.ox.ac.uk/fox-got-you
 
Description UTC Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Short talks at careers day
Year(s) Of Engagement Activity 2015
 
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.
Year(s) Of Engagement Activity 2015,2017
URL http://www.sciencefestival.cam.ac.uk/about/past-festivals/2015-cambridge-science-festival
 
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 one Year 10 student (age 15) to the Unit for a week's work experience/shadowing in various research groups/environments, chaperoned throughout by individual members of the Unit. Presentation by the visitor at the end of the week.
Year(s) Of Engagement Activity 2016,2017