Exploring mitochondrial metabolism in health and disease using targeted biological chemistry (360G-Wellcome-338576_Z_25_Z)

The importance of mitochondria in physiology and pathology is clear, but a major block on progress has been the difficulty of assessing these pathways in vivo. Furthermore, despite their many roles in pathology, mitochondria are neglected as a drug target. A major impediment to both understanding how mitochondria work and to the development of mitochondrial pharmacology is the challenge of targeting probe, bioactive or therapeutic molecules to mitochondria in vivo. To address these unmet needs the Murphy and Hartley labs will use chemical biology approaches to target molecules to mitochondria in vivo. The core of this application is the established collaboration between the mitochondrial biology (Murphy) and synthetic chemistry (Hartley). This partnership spans the design and synthesis of probe and therapeutic molecules and their assessment in vitro and in vivo. Together with our key collaborators we then utilise these chemical tools to explore mitochondrial dysfunction in vivo and ex vivo using a range of animal models of human pathologies. We have separated our research questions into two aims: to address unresolved questions in mitochondrial biology using targeted biological chemistry, and to develop new chemical biology approaches to investigate mitochondria to address unmet needs that are hindering progress.