Mammalian complex I (NADH:ubiquinone oxidoreductase) is a crucial mitochondrial enzyme. It oxidises NADH from the tricarboxylic acid cycle, fatty-acid oxidation and glycolysis, reduces ubiquinone for the rest of the respiratory chain, and transports protons across the inner mitochondrial membrane to support ATP synthesis. It is also a major contributor to cellular reactive oxygen species production and oxidative stress. With nine redox cofactors and 44 different subunits, encoded on both the nuclear and mitochondrial genomes, mammalian complex I is one of the largest, most complicated enzymes in the cell. We aim to determine the structure of mammalian complex I, and its mechanisms of catalysis and reactive oxygen species production.
Complex I is linked to medicine on many different levels: from mutations in its subunits and assembly factors that cause mitochondrial diseases, through reactive oxygen species production and oxidative damage (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. We aim to build on our knowledge of structure and mechanism to understand human complex I dysfunctions on the molecular level, and to elucidate the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions.
MRC ITTP (Integrative Toxicology Training Partnership) studentship
Mitochondrial toxicity in human drug induced liver injury: defining contributions and mechanisms to inform safer drug development
The MRC ITTP studentship, commencing in October 2021, will be awarded on a competitive basis to the successful eligible applicant. The studentship pays for Cambridge University and College fees, and covers living expenses. This Ph D studentship is awarded for four years of study.
Eligibility: students who either are UK nationals or have established UK residency.
About the project:
Adverse drug reactions cause side-effects in patients, impede the development of new medicines, and slow therapeutic advances. Drug induced liver injury (DILI) is a serious adverse drug reaction that causes more than 50% of acute liver failure cases, and a common driver of drug attrition in phase I-III clinical trials across therapeutic areas (1). To better understand and minimise DILI it is essential to understand the molecular toxicity mechanisms of compounds that cause it, so they can be avoided in new candidate medications. Off-target inhibition of mitochondrial function (2) is a recognised contributor to clinical DILI. However, the true scale of mitochondrial toxicity in DILI has not been rigorously investigated, and there is little mechanistic understanding of how DILI compounds affect mitochondrial function to drive hepatocyte dysfunction.
This studentship will address pivotal questions in mitochondrial DILI. The project is a collaboration between the MRC Mitochondrial Biology (3) and Toxicology Units (4) (University of Cambridge) and AstraZeneca, and the student will be expected to work closely with researchers across both institutions. The studentship will be hosted at the MRC Mitochondrial Biology Unit. The student will work in both University and AstraZeneca laboratories in Cambridge and is expected to engage fully with both the academic and pharma research communities.
During the studentship, the student will learn a robust set of techniques that are fundamental in biomedical research, including a broad panel of enzyme and cellular assays, biochemical methods of sample preparations, cell culture (including primary cells at biosafety level 2) and experiments that assess cellular homeostasis and function. These methods will lay the foundation for detailed mechanistic studies to provide a balanced portfolio of training, consolidation and challenge objectives. By advancing understanding of the homeostatic thresholds and adverse outcome pathways of mitochondrial toxicity in hepatocytes the project will aim to transform understanding of mitochondrial DILI and support safer preclinical drug development.
1. Weaver et al. (2020). Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models. Nat. Rev. Drug Discov. 19, 131– 148.
2. Will Y, Shields JE , Wallace, KB. (2019). Drug-induced mitochondrial toxicity in the geriatric population: Challenges and future directions. Biology 8, 32.
Please submit a covering letter and a CV, including the names of two academic referees, by 1 March 2021, by email to: .
Enquiries and requests for further information may also be made to this address.