I am a DPhil student working under the supervision of Prof Keith Channon and Dr Mark Crabtree in the Division of Cardiovascular Medicine. The main aim of my thesis is to understand the role of the molecule tetrahydrobiopterin (BH4) in mitochondrial function and redox signalling in cellular models of cardiovascular disease.
BH4 has a well characterised role in regulating NO and ROS generation from the NOS enzymes. Loss of BH4 leads to diminished NO and elevated ROS synthesis from NOS, and is observed in cardiovascular diseases, however BH4 supplementation has so far had limited success. Novel roles for BH4 beyond its enzyme cofactor functions are undefined, but a major NOS-independent source of elevated ROS has been observed in cellular models lacking BH4 in our lab. My DPhil project has identified the mitochondria as the major source of elevated ROS in a BH4 deficient endothelial cell model, and has shown changes in mitochondrial BH4 content, mitochondrial size and metabolism. Interestingly, a NOS independent source of elevated ROS is also observed in macrophages lacking BH4, and future work will determine whether BH4 affects mitochondrial function and redox signalling in these cells. These studies enhance our understanding of BH4 dependent signalling and highlight the mitochondria as a potential therapeutic target in BH4 deficient patients.