Mitochondria are not only the energy factories of the cell, but also involved in regulating many other cell functions, including cell death. The production of energy in healthy cells depends on the availability of oxygen and nutrients. However, in many diseases, e.g. heart attacks or cancer, oxygen and nutrient supplies are limited due to an obstructed or inefficient vasculature. This fundamentally changes the metabolic networks that the cells use to processes nutrients, and, in normal conditions generate ATP. Interestingly, changing cellular environments can also alter the mitochondrial shapes by fusion or fission of mitochondria, and, by transport of the mitochondria throughout the cells. However, little is understood about the implications of these physical, geometrical changes on mitochondrial functions. Yet, by changing the organisation of the mitochondria, the cells thereby inevitably change the molecules within them. Therefore, the chemical dynamics of the metabolic and signalling molecules cannot be uncoupled from the biophysical and geometric changes of the mitochondria.
In this project, we will develop an interdisciplinary systems approach to understand the interplay of mitochondrial dynamics with metabolic and cell death regulating pathways.
This approach will place molecular, biophysical and geometric features of metabolism and cell death regulation on an equal footing and lead to a holistic view of the regulation of these important cell phenotypes. The fundamental aim is to reveal how these features regulate life and death of cells together.
We will use confocal imaging, metabolic flux analysis and mathematical models to uncover the coupling of dynamic mitochondrial organisation, energy production and cell death to predict how mitochondrial organisation is altered in stressed states, and how this alteration may contribute to cell death.