In situ structural biology of cellular adaptation

About the project

About the Project A 2027 Crick-University College London Joint PhD project with Peter Rosenthal (Crick) and Amandine Marechal (UCL). Please note: to apply to this project, candidates must be eligible for home tuition fee status. Project background and description Cells respond to changes in their environment by rapid and coordinated adaptation of metabolism and organelle function. Mitochondria are central to this response, acting not only as the primary source of ATP through oxidative phosphorylation, but also as hubs for metabolite production, redox signalling, and cell fate decisions. Adaptation is mediated by coordinated remodelling of the respiratory chain within the inner mitochondrial membrane. Individual respiratory complexes associate with one another to form larger assemblies known as supercomplexes, and the extent and nature of this association can shift according to cellular conditions such as hypoxia, infection, or other metabolic stress. This project will investigate how respiratory complex association and supercomplex formation are regulated, and how changes in membrane organisation itself contribute to rewiring metabolism to match cellular demand. The student will address these questions using a multidisciplinary approach combining in situ cryo-electron tomography, metabolic and respirometry-based assays, and molecular perturbation strategies on yeast and human cell lines. In situ cryo-electron tomography will visualise the organisation of respiratory chain complexes within native mitochondrial membranes. These structural insights may be integrated with biophysical and proteomic analyses to establish how changes in mitochondrial membrane organisation reshape energy production and to identify key regulatory proteins. The project will study the structural and functional consequences of respiratory supercomplex remodelling for respiration, redox balance, and cellular adaptation, possibly extending to physiologically relevant contexts such as infection. This project will provide advanced training in electron cryomicroscopy, in situ structural biology and bioenergetics within a collaborative research environment. Integrating structural and metabolic perspectives, it will uncover fundamental principles governing mitochondrial adaptation to environmental and metabolic stress, with broad relevance to diseases including infection, cancer, and ischaemic disorders, and has the potential to reveal new avenues for targeting mitochondrial function. Candidate background This project is suitable for students with an interest in mitochondrial biology, metabolism, or cellular adaptation to stress including viral infection and with a strong background in biochemistry, cell biology, microbiology, biophysics, structural biology or a related discipline. Students with an interest in methodological aspects of the projects will also be considered. Prior experience in experimental protein biochemistry, cell culture, computational analysis of biological data or cryo-electron microscopy will be advantageous, although experience in all areas is not required. Candidates with an interest in structural biology, bioenergetics or membrane biology are especially encouraged to apply. The project combines functional and structural approaches across UCL and the Francis Crick Institute and will therefore particularly benefit candidates who are motivated to work in an interdisciplinary environment and to develop expertise across complementary techniques. We particularly encourage applications from candidates who are motivated to understand how molecular mechanisms are linked to cellular function, and who are eager to tackle fundamental questions at the interface of structure and metabolism. Curiosity, initiative, and a willingness to engage with diverse experimental approaches will be key to success in this project. Lab-specific question Identify a finding, technique or approach from your previous research that you think could be relevant to our work. How might you apply or develop this in a PhD project in our lab?

Research areas