Mitochondrial Dysfunction and Cell Death in Disease

Our group’s research is focussed on the elucidation of critical mechanisms of mitochondrial dysfunction which determine cell death pathways underlying human disease. In recent studies we have shown that pancreatic acinar cell damage induced by toxins that cause acute pancreatitis involves excessive calcium entry via store-operated (Orai) channels which causes calcium overload of the mitochondria. In response to high mitochondrial matrix calcium there is formation of the mitochondrial permeability transition pore (MPTP), a mega pore modulated by cyclophilin D that allows movement of solutes across mitochondrial membrane and depolarises mitochondria preventing effective formation of ATP necessary for vital cellular processes. Ultimately cells die by necrosis, the extent of which determines the severity of clinical disease, although recent results from our laboratory suggest that necroptosis (a "programmed necrosis") may also play a role. Inhibition of Orai or prevention of MPTP formation, using genetic modification or pharmacological inhibition, prevented acute pancreatitis in vitro and in vivo. One of our current areas of interest is the understanding of bioenergetic changes and protein modifications that determine mitochondrial dysfunction and determine cell death modalities; multiple experimental approaches are used, including use of genetic models in Seahorse XF analysis of mitochondrial bioenergetics, confocal microscopy and plate-reader approaches coupled to in vivo models of disease. Our studies also benefit from use of human samples where appropriate.

Applications accepted all year round but fee bursary might be available for applications received by the end of April 2017.