The Francis Crick Institute Limited
Devine and Hodgkinson Lab | Exploring subcellular mitochondrial heterogeneity in
The Francis Crick Institute Limited, Devine, Texas, United States, 78016
A 2026 Crick PhD project with Mike Devine and Alan Hodgkinson.
Project background and description
Mitochondria are essential organelles responsible for producing cellular energy and regulating processes such as cell signalling and death. While it is well established that mitochondrial function varies between tissue types, much less is known about how mitochondria differ within the distinct regions of a single cell. This gap in understanding is especially important in the context of neurons, which have highly polarised structures, including the cell body, dendrites and synapses, that each have unique functional roles and energetic demands. In neurons, mitochondria must adapt to the specific needs of their local environment. For instance, mitochondria at synapses are critical for supporting the energy-intensive process of neurotransmission, whereas those in the cell body contribute more broadly to maintaining cell viability and regulating intracellular communication. These regional differences in function suggest that mitochondria themselves may be specialised depending on their subcellular location, but a clear map of this diversity in human neurons is lacking. This PhD project aims to systematically explore the regional specialisation of mitochondria within human neurons. Using induced pluripotent stem cell (iPSC) technology, we will generate both cortical and dopaminergic neurons (cell types relevant to brain health and disease) and grow them in custom-designed microfluidic chambers that allow us to physically separate different parts of the same cell. This will enable us to independently isolate mitochondria from neuronal compartments and compare their molecular features and functional properties. To characterise regional mitochondrial diversity, we will combine molecular and functional assays to examine mitochondrial DNA content, gene expression, protein composition and metabolic activity in each compartment. By comparing findings across different neuronal types, the project will provide insight into whether and how mitochondrial specialisation is tailored to specific cellular roles. Depending on the interests of the student, this project could incorporate analysis of mitochondrial specialisation in neuronal models of disease (e.g. Parkinson’s or Alzheimer’s). This interdisciplinary research will combine cell culture, neurobiology and genomics to answer a fundamental question about human cell biology: how do mitochondria vary within a single cell to meet the specialised demands of different subcellular regions? The successful candidate will gain hands-on experience with stem cell differentiation, neuronal culture systems and a range of molecular profiling techniques, along with the opportunity to develop skills in data analysis, integration and interpretation. Understanding regional mitochondrial specialisation could reshape how we think about mitochondrial biology in complex human cells and could shed light on how disruptions to this system contribute to brain disorders. As such, this project offers a unique opportunity to explore a largely uncharted aspect of human biology while developing a strong foundation in experimental and analytical research. Candidate background
This project would be particularly suited to candidates that are interested in working across disciplines. Some experience of wet lab work (e.g. iPSC neuronal models, or any cell biology projects) and/or computational methods would be helpful, although specific training for technical aspects of the project will be provided. The main attributes would be a willingness to learn, and a curiosity for the problems that we are working on. References
Ali, A.T., Boehme, L., Carbajosa, G., Seitan, V.C., Small, K.S. and Hodgkinson, A. (2019) Nuclear genetic regulation of the human mitochondrial transcriptome. eLife 8: e41927. PubMed abstract Ali, A.T., Idaghdour, Y. and Hodgkinson, A. (2020) Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes. Communications Biology 3: 147. PubMed abstract Devine, M.J. and Kittler, J.T. (2018) Mitochondria at the neuronal presynapse in health and disease. Nature Reviews Neuroscience 19: 63-80. PubMed abstract Tian, R., Gachechiladze, M.A., Ludwig, C.H., Laurie, M.T., Hong, J.Y., Nathaniel, D., . . Kampmann, M. (2019) CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104: 239-255 e212. PubMed abstract Vaccaro, V., Devine, M.J., Higgs, N.F. and Kittler, J.T. (2017) Miro1-dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity. EMBO Reports 18: 231-240. PubMed abstract
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Mitochondria are essential organelles responsible for producing cellular energy and regulating processes such as cell signalling and death. While it is well established that mitochondrial function varies between tissue types, much less is known about how mitochondria differ within the distinct regions of a single cell. This gap in understanding is especially important in the context of neurons, which have highly polarised structures, including the cell body, dendrites and synapses, that each have unique functional roles and energetic demands. In neurons, mitochondria must adapt to the specific needs of their local environment. For instance, mitochondria at synapses are critical for supporting the energy-intensive process of neurotransmission, whereas those in the cell body contribute more broadly to maintaining cell viability and regulating intracellular communication. These regional differences in function suggest that mitochondria themselves may be specialised depending on their subcellular location, but a clear map of this diversity in human neurons is lacking. This PhD project aims to systematically explore the regional specialisation of mitochondria within human neurons. Using induced pluripotent stem cell (iPSC) technology, we will generate both cortical and dopaminergic neurons (cell types relevant to brain health and disease) and grow them in custom-designed microfluidic chambers that allow us to physically separate different parts of the same cell. This will enable us to independently isolate mitochondria from neuronal compartments and compare their molecular features and functional properties. To characterise regional mitochondrial diversity, we will combine molecular and functional assays to examine mitochondrial DNA content, gene expression, protein composition and metabolic activity in each compartment. By comparing findings across different neuronal types, the project will provide insight into whether and how mitochondrial specialisation is tailored to specific cellular roles. Depending on the interests of the student, this project could incorporate analysis of mitochondrial specialisation in neuronal models of disease (e.g. Parkinson’s or Alzheimer’s). This interdisciplinary research will combine cell culture, neurobiology and genomics to answer a fundamental question about human cell biology: how do mitochondria vary within a single cell to meet the specialised demands of different subcellular regions? The successful candidate will gain hands-on experience with stem cell differentiation, neuronal culture systems and a range of molecular profiling techniques, along with the opportunity to develop skills in data analysis, integration and interpretation. Understanding regional mitochondrial specialisation could reshape how we think about mitochondrial biology in complex human cells and could shed light on how disruptions to this system contribute to brain disorders. As such, this project offers a unique opportunity to explore a largely uncharted aspect of human biology while developing a strong foundation in experimental and analytical research. Candidate background
This project would be particularly suited to candidates that are interested in working across disciplines. Some experience of wet lab work (e.g. iPSC neuronal models, or any cell biology projects) and/or computational methods would be helpful, although specific training for technical aspects of the project will be provided. The main attributes would be a willingness to learn, and a curiosity for the problems that we are working on. References
Ali, A.T., Boehme, L., Carbajosa, G., Seitan, V.C., Small, K.S. and Hodgkinson, A. (2019) Nuclear genetic regulation of the human mitochondrial transcriptome. eLife 8: e41927. PubMed abstract Ali, A.T., Idaghdour, Y. and Hodgkinson, A. (2020) Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes. Communications Biology 3: 147. PubMed abstract Devine, M.J. and Kittler, J.T. (2018) Mitochondria at the neuronal presynapse in health and disease. Nature Reviews Neuroscience 19: 63-80. PubMed abstract Tian, R., Gachechiladze, M.A., Ludwig, C.H., Laurie, M.T., Hong, J.Y., Nathaniel, D., . . Kampmann, M. (2019) CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104: 239-255 e212. PubMed abstract Vaccaro, V., Devine, M.J., Higgs, N.F. and Kittler, J.T. (2017) Miro1-dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity. EMBO Reports 18: 231-240. PubMed abstract
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