The Role of Mitochondria in Pulmonary Hypertension-Warburg Redux
Throughout my career I have benefited from the superb mentorship of Dr. E Kenneth Weir, from an array of talented collaborators, and from the contributions of masterful technicians and staff scientists. I have also enjoyed mentoring many talented trainees who developed into independent scientists and leaders in their own right. This lecture summarizes work of these individuals over the past 25 years. We initially identified a mechanism of hypoxic pulmonary vasoconstriction (HPV) and gradually recognized that this mechanism was subverted in proliferative disorders, including pulmonary arterial hypertension (PAH). We showed that mitochondria in pulmonary artery smooth muscle cells (PASMC) act as oxygen sensors by generating reactive oxygen species (ROS) that regulate oxygen-sensitive potassium channels (e.g. Kv1.5) and thereby control vascular tone. More recently we found that acquired disorders of mitochondrial function and structure are important in the pathogenesis of PAH. We discovered that the mitochondria-ROS-HIF-1α-Kv1.5 pathway is disordered in PAH such that cells perceive themselves as hypoxic, despite adequate PO2. This hypoxic mitochondrial-metabolic transformation confers a survival advantage, leading to excessive cell proliferation and impaired apoptosis. Despite adequate oxygen, PAH PASMC have impaired oxidative glucose metabolism and enhanced glycolytic metabolism, due to activation of pyruvate dehydrogenase kinase (PDK) and HIF-1α. This glycolytic shift constitutes a survival mechanism for PAH PASMC and endothelial cells (thus Warburg's hypothesis redux). We have identified several mitochondrial abnormalities that may offer therapeutic targets: (1) There is pathologic PDK activation that inhibits oxidative metabolism and favors glycolysis. Dichloroacetate, a prototypic PDK inhibitor, normalizes the mitochondria-ROS-HIF-1α-Kv1.5 pathway and regresses several experimental models of PAH. (2) There is a heritable, epigenetic downregulation of mitochondrial superoxide dismutase (SOD2), due to methylation of CpG islands in the SOD2 gene. Therapies that reverse epigenetic silencing of SOD2 or supplement SOD may be feasible. (3) Normal mitochondria are fused into a reticulum by fusogenic proteins (notably mitofusin-2). Mitofusin-2 also regulates cell proliferation. In PAH there is an increased ratio of mitochondrial fission to fusion, due in part to reduced mitofusin-2 levels. Fusogenic mitochondrial therapies are being developed.
- © 2010 by American Heart Association, Inc.