Mitochondrial complex I: An intricate energy-converting machine, a cornerstone of mitochondrial metabolism, and a locus of mitochondrial dysfunction and disease
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Dysfunctions of mitochondrial complex I, the first of four energy-converting complexes that power the cell to produce ATP by oxidative phosphorylation, cause many mitochondrial diseases. Following the ‘resolution revolution’ in cryo-electron microscopy (cryoEM) the structure of mammalian complex I has been solved, but many key aspects of how the enzyme works remain unknown. It is further unclear how it is regulated, repaired or replaced; how its structure, function or assembly are affected by clinically-identified mutations; or how reactive oxygen species, drugs or toxins affect its catalysis and function in the cell. Even when a mutation in a well-characterised complex I gene is established as the direct cause of a mitochondrial disease, the pathological mechanisms that define the pathways from the molecular defect to the clinical symptoms are poorly understood.
The aims of the Mitochondrial Complex I programme are to define and understand the molecular structure, function and dysfunction of mammalian complex I, and to exploit and apply this basic knowledge to understand complex I in vivo, elucidate disease mechanisms, support clinical diagnoses, and contribute to the development of therapeutic strategies against both primary diseases and complex multifactorial disorders involving complex I.
The aims of the Mitochondrial Complex I programme are to define and understand the molecular structure, function and dysfunction of mammalian complex I, and to exploit and apply this basic knowledge to understand complex I in vivo, elucidate disease mechanisms, support clinical diagnoses, and contribute to the development of therapeutic strategies against both primary diseases and complex multifactorial disorders involving complex I.
Technical Summary
Mitochondrial complex I (NADH:ubiquinone oxidoreductase) powers ATP synthesis by oxidative phosphorylation, exploiting the energy from reduction of ubiquinone by NADH to drive protons across the energy-transducing inner membrane. Being also required to maintain the redox status of the mitochondrial NAD+ pool to keep the tricarboxylic acid cycle and ß-oxidation running, it is a keystone of mitochondrial metabolism and crucial for the survival of human cells. Consequently, mutations in its subunits and assembly factors that impact on its structure, function or biogenesis cause mitochondrial diseases, it is a drug target in diabetes, ischaemia-reperfusion (IR) injury and cancer, and complex I-linked drug toxicity compromises drug discovery programmes. Understanding the function and dysfunction 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, mechanism and assembly is required to underpin biomedical studies of complex I in mitochondrial and cellular systems of greater complexity. The Mitochondrial Complex I group aims to develop and apply this basic knowledge to understand and address the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions.
People |
ORCID iD |
Judy Hirst (Principal Investigator) |
Publications
Agip AA
(2023)
Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster.
in eLife
Chung I
(2022)
Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
in Nature communications
Chung I
(2022)
Ubiquinone-10 binding to mammalian respiratory complex I and conformational transitions associated with Q-site occupancy
in Biochimica et Biophysica Acta (BBA) - Bioenergetics
Chung I
(2022)
Making the leap from structure to mechanism: are the open states of mammalian complex I identified by cryoEM resting states or catalytic intermediates?
in Current opinion in structural biology
Grba DN
(2023)
Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
in Science advances
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00028/1 | 01/04/2022 | 31/03/2027 | £3,998,000 | ||
MC_UU_00028/2 | Transfer | MC_UU_00028/1 | 01/04/2022 | 31/03/2027 | £3,700,000 |
MC_UU_00028/3 | Transfer | MC_UU_00028/2 | 01/04/2022 | 31/03/2027 | £3,567,000 |
MC_UU_00028/4 | Transfer | MC_UU_00028/3 | 01/04/2022 | 31/03/2027 | £3,947,000 |
MC_UU_00028/5 | Transfer | MC_UU_00028/4 | 01/04/2022 | 31/03/2027 | £3,214,000 |
MC_UU_00028/6 | Transfer | MC_UU_00028/5 | 01/04/2022 | 31/03/2027 | £3,000,000 |
MC_UU_00028/7 | Transfer | MC_UU_00028/6 | 01/04/2022 | 31/03/2027 | £1,630,000 |
MC_UU_00028/8 | Transfer | MC_UU_00028/7 | 01/04/2022 | 04/05/2025 | £433,000 |
MC_UU_00028/9 | Transfer | MC_UU_00028/8 | 01/04/2022 | 31/03/2027 | £390,000 |
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 | Inhibition of complex I by rotenone |
Organisation | University of Cambridge |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Experimental design, investigation, analyses, writing, review, editing manuscript. |
Collaborator Contribution | Experimental design, investigation, analyses, writing, review, editing manuscript. |
Impact | Russell, D. A., Bridges, H. R., Serreli, R., Kidd, S. L., Mateu, N., Osberger, T. J., Sore, H. F., Hirst, J. & Spring, D. R. (2020) Hydroxylated rotenoids selectively inhibit the proliferation of prostate cancer cells. J. Nat. Prod. 83, 1829-1845. |
Start Year | 2017 |
Description | Integrative Toxicology Training Partnership - to explore off-target complex I inhibition in drug-induced liver injury (DILI) |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | To interrogate the AstraZeneca DILI compound library to establish the prevalence of OxPhos and complex I toxicity in clinical DILI and to benchmark the AstraZeneca high-throughput screen for its ability to identify OxPhos inhibitors. Analyses will be undertaken to build understanding of how in vitro mitochondrial toxicity translates and is predictive of clinical liver injury. Studies will be undertaken to establish the threshold of mitochondrial damage that impairs the function of human and rat primary hepatocytes. Through further analyses, we hope to identify compensatory pathways as future targets for mitigating toxicity, and new candidate biomarkers for mitochondrial injury. |
Collaborator Contribution | Scientific expertise; access to the DILI compound library and provision of rat primary hepatocytes (AstraZeneca). |
Impact | No impact yet. |
Start Year | 2021 |
Description | Off-target inhibition of complex I |
Organisation | Medical Research Council (MRC) |
Department | MRC Toxicology Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conceptuatlisation, supervision, investigation, writing, review and editing, |
Collaborator Contribution | Formal analysis, investigation, methodology, writing, review, editing, supervision, conceptualisation |
Impact | Stephenson, Z. A., Harvey, R. F., Pryde, K. R., Mistry, S., Hardy, R. E., Serreli, R., Chung, I., Allen, T. E. H., Stoneley, M., MacFarlane, M., Fischer, P. M., Hirst, J., Kellam, B. & Willis, A. E. (2020) Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I. eLife, 9, e55845. |
Start Year | 2017 |
Description | Off-target inhibition of complex I |
Organisation | University of Nottingham |
Department | School of Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conceptuatlisation, supervision, investigation, writing, review and editing, |
Collaborator Contribution | Formal analysis, investigation, methodology, writing, review, editing, supervision, conceptualisation |
Impact | Stephenson, Z. A., Harvey, R. F., Pryde, K. R., Mistry, S., Hardy, R. E., Serreli, R., Chung, I., Allen, T. E. H., Stoneley, M., MacFarlane, M., Fischer, P. M., Hirst, J., Kellam, B. & Willis, A. E. (2020) Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I. eLife, 9, e55845. |
Start Year | 2017 |
Description | Access Students from Cambridge Regional College |
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 | 11 Access students from Cambridge Regional College visited the MBU for a "Biology Masterclass", a visit to the fly laboratory and a "meet the scientists" session, where hands-on "festival" activities were available. |
Year(s) Of Engagement Activity | 2022 |
Description | Big Biology Day 2022 |
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 | Hands on, interactive activities showcasing the MBU's research on mitochondria, careers advice. Activities will include our MITOTrumps card game, demonstrations using fruit flies and mitochondrial pinball. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.mrc-mbu.cam.ac.uk/news/mrc-mbu-big-biology-day-2022 |
Description | Website and social media |
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 is promoted on the MBU's website and via social media channels, such as Facebook and Twitter. This leads to various forms of engagement - increased awareness, requests for further information, potential collaborations etc. |
Year(s) Of Engagement Activity | 2022,2023 |
URL | https://www.mrc-mbu.cam.ac.uk/research-groups/hirst-group |