Abstract 448: Tetrahydrobiopterin Rescues Mitochondrial Dysfunction by Regulating Mitochondrial Biogenesis and Oxidative Phosphorylation
The multifunctional cofactor tetrahydrobiopterin (BH4) has antioxidant effects, and low levels of BH4 expression are implicated in various cardiovascular diseases involving mitochondrial dysfunction. We investigated the role of BH4 in the regulation of cardiac mitochondrial function using sepiapterin reductase knockout (Spr–) mice as a model of BH4 deficiency. Based on systematic data-integrative analysis of the mitochondrial proteome, we found that BH4 deficiency resulted in significant remodeling of oxidative phosphorylation, which impaired mitochondrial membrane potential, oxygen consumption, and ATP production, and induced oxidative stress in mitochondria DNA, leading to cardiac contractile dysfunction. Moreover, the expression of major regulators of mitochondrial biogenesis and respiration, such as PGC1-α and mtTFA, was reduced by BH4 deficiency. Finally, we confirmed that BH4 supplementation could rescue cardiac mitochondrial biogenesis and oxidative phosphorylation, which demonstrates the therapeutic potential of BH4 for the treatment of cardiovascular diseases involving mitochondrial dysfunction.
 Kim, H.K., Ha, S.H., and Han, J. (2010). Potential therapeutic applications of tetrahydrobiopterin: from inherited hyperphenylalaninemia to mitochondrial diseases. Ann N Y Acad Sci 1201, 177-182.
 Yang, S., Lee, Y.J., Kim, J.M., Park, S., Peris, J., Laipis, P., Park, Y.S., Chung, J.H., and Oh, S.P. (2006). A murine model for human sepiapterin-reductase deficiency. Am J Hum Genet 78, 575-587.
- © 2012 by American Heart Association, Inc.