A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance

摘要: The redox co-factor tetrahydrobiopterin (BH4) regulates nitric oxide (NO) and reactive oxygen species (ROS) production by endothelial NOS (eNOS) is an important redox-dependent signalling molecule in the endothelium. Loss of BH4 observed cardiovascular disease (CVD) states results decreased NO increased superoxide (O2-) generation via eNOS uncoupling. Genetic mouse models augmented synthesis have shown proof concept that can alter CVD pathogenesis. However, clinical trials therapy vascular been limited systemic oxidation, highlighting need to explore wider roles find novel therapeutic targets. In this study, we aimed elucidate effects deficiency on mitochondrial function bioenergetics using targeted knockdown synthetic enzyme, GTP Cyclohydrolase I (GTPCH). Knockdown GTPCH >90% led marked loss cellular a striking induction O2- mitochondria murine cells. This effect was likewise BH4-depleted fibroblasts devoid NOS, indicating NOS-independent role for signalling. Moreover, BH4-dependent, mitochondria-derived ROS further oxidised BH4, concomitant with changes thioredoxin glutathione antioxidant pathways. These were accompanied modest increase size, mildly attenuated basal respiratory function, proteome metabolome, including accumulation TCA intermediate succinate. Taken together, these data reveal regulation bioenergetic metabolism.