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Crosstalk of Mitochondrial Dynamics, Intracellular Mechanics and Cellular Energetics


Project Description

Mitochondria are the energy factories of cells, and their function underlies virtually all cell functions. Moreover, mitochondrial dysfunction underlies a wide spectrum of diseases, including diabetes, heart failure, bipolar disorder and non-alcoholic fatty liver disease (NAFLD). Therefore, mitochondrial function is seen as a potential therapeutic target for many “energy starvation” related disease conditions. Research shows that mitochondria appear as highly dynamic, and their positions are constantly rearranged within a cell. Moreover, they are not uniformly positioned within a cell, but may exhibit patterns that influence intracellular signalling dynamics and information processing (1). While it is intriguing to speculate that their spatial positioning within a cell will depend on the localised energy needs of a cell, little is known about the precise regulation of mitochondrial positioning.

Naturally, directed repositioning of any intracellular components depends on mechanical properties, such as molecular motor activity. Moreover, the spatial rearrangement of intracellular mechanical structures, the cytoskeleton, is expected to influence the positioning of mitochondria. Intriguingly, the cytoskeleton is itself dynamic, and depends strongly on intracellular energy.

In this project, we will investigate the tri-directional crosstalk between the spatio-temporal regulation of mitochondria, the cytoskeleton and intracellular energy. We will analyse trajectories of mitochondria and show how the distributions of these trajectories change in dependence on cell mechanical properties and intracellular energy states during physiological and pathophysiological conditions. Information about viscoelastic properties of the cells will be extracted from these trajectories (2). We will also develop new stochastic models that can accurately describe these trajectories, and that can explain how important features of mitochondrial organisation interplay with cell mechanics and energetics. This model will predict how mitochondria organise themselves in cells, and therefore allow us to gain unprecedented insights into the system-level regulation of mitochondria and the interdependence with cell mechanics and cellular energetics.

While this project will focus primarily on mathematical modelling, the candidate will benefit from a close interaction with experimentalists to validate the model predictions and learn to analyse biological data from various developmental or disease states. For example, we will analyse data from diverse biological systems including heart disease cell models, but also plant cells, and determine whether this novel technique describes universal features of the energetic regulation of cells. These novel findings may potentially aid future development of drug targets to improve mitochondrial function (3, 4).

Methods: Stochastic Processes, Data Analysis, Mathematical Modelling, Mechanics

Requirements: An excellent 1st class degree in Mathematics, Theoretical Physics, Engineering or related subjects, and motivation to work in an interdisciplinary environment. Familiarity with some of the abovementioned methods is a plus, but the willingness to learn new methods is more essential.

Supervisory Team:
The host environment will provide the student an excellent training platform from research experts nationally and internationally, which spans from Engineers and Mathematical Biologists to Biomedical Researchers working on mitochondria:

Main supervisor: Fabian Spill, School of Mathematics, University of Birmingham, . Expert on Mathematical Biology, Systems Biology and Mechanobiology.

Main supervisor: Vijay Rajagopal, Department of Biomedical Engineering, University of Melbourne, .
Expert on cardiac cell modelling, mitochondrial organisation and systems biology.

Co-supervisor: Iain Johnston, School of Biosciences, University of Birmingham. Expert of mitochondrial regulation in Plants.

Co-supervisor: Melanie Madhani, Institute of Cardiovascular Sciences, University of Birmingham. Expert on role of mitochondria in cardiac diseases and metabolism.

Collaborator: Michael Mak, Department of Bioengineering, Yale University. Expert on using mitochondrial dynamics to infer cell mechanical properties.

Collaborator: David Stroud, School of Biomedical Sciences, University of Melbourne. Expert on mitochondrial systems biology.

Funding Notes

A fully-funded studentship, which includes tax-free Doctoral Stipend of £15,009* per annum, is available for Home/EU and Overseas students on this Joint PhD programme between the University of Birmingham and the University of Melbourne for October 2019 start. For students who are to be hosted by the University of Melbourne, the scholarship rate will be $AUD30,000 p.a. and will include provision for a return trip to Birmingham.
*subject to inflationary variation

References

1. Ghosh S, Tran K, Delbridge LMD, Hickey AJR, Hanssen E, Crampin EJ, et al. Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture. PLOS Computational Biology. 2018;14(12):e1006640.
2. Mak M, Anderson S, McDonough MC, Spill F, Kim JE, Boussommier-Calleja A, et al. Integrated Analysis of Intracellular Dynamics of MenaINV Cancer Cells in a 3D Matrix. Biophysical Journal. 2017;112(9):1874-84.
3. Noordali H, Loudon BL, Frenneaux MP, Madhani M. Cardiac metabolism — A promising therapeutic target for heart failure. Pharmacology & Therapeutics. 2018;182:95-114.
4. Borgognone A, Prompunt E, Ed Rainger G, Chimen M, Worrall SM, Watson SP, et al. Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation. Cardiovascular Research. 2018;114(10):1313-23.

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