Mitochondrial Complex I

Lead Research Organisation: University of Cambridge

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

10 25 50
 
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 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 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 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 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 involved activities hosted by 2 members of my research group.
Year(s) Of Engagement Activity 2018
 
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 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