Exploring mitochondrial metabolism in health and disease using targeted biological chemistry (360G-Wellcome-220257_Z_20_Z)

The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo: A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways? B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies? C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?