Mitochondrial Dysfunction and Congenital Heart Disease

The pulmonary vasculature in infants born with congenital heart defects that cause increased Pulmonary Blood Flow (PBF) is subjected to pathologic mechanical forces, including chronically increased shear stress, resulting in early functional abnormalities of the vascular endothelium. These functional abnormalities occur prior to the development of well-described morphologic changes. However, little is known about the factors that transduce the abnormal shear forces associated with increased PBF into abnormal vascular function and reactivity. Recently the disruption of mitochondrial function has been identified as a new mechanism that leads to the development of pulmonary endothelial dysfunction. This is a complex process that involves post-translational regulation of multiple proteins and the mitochondrial redistribution of uncoupled endothelial nitric oxide synthase (eNOS) resulting in the disruption of carnitine metabolism and subsequently mitochondrial bioenergetics. As both eNOS and GTP cyclohydrolase I, the rate limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, are chaperoned by hsp90 this results in a “feed-forward” signaling cascade in which eNOS becomes progressively more uncoupled resulting in pulmonary endothelial dysfunction. This review will discuss the current knowledge in the field, the limitations in our understanding this complex process, and the potential for targeting mitochondrial function in the treatment of children born with congenital heart defects that result in increased pulmonary blood flow.